@misc{
 title = {Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin},
 type = {misc},
 year = {2020},
 source = {bioRxiv},
 id = {93dfbda1-07c0-3e23-81eb-4ba42825bd0f},
 created = {2021-02-14T23:59:00.000Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2021-11-18T21:35:19.809Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {true},
 abstract = {The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.  Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50=11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.},
 bibtype = {misc},
 author = {Jiang, D. and Tonggu, L. and Gamal El-Din, T.M. and Banh, R. and Pomès, R. and Zheng, N. and Catterall, W.A.},
 doi = {10.1101/2020.12.28.424592}
}

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50=11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.

@article{
 title = {The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate},
 type = {article},
 year = {2020},
 volume = {152},
 id = {cdea2954-9524-3e4a-8220-566a4f76e79c},
 created = {2019-12-19T23:59:00.000Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2021-02-27T01:36:15.981Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {true},
 abstract = {© 2019 Yamashita et al. Store-operated Orai1 channels regulate a wide range of cellular functions from gene expression to cell proliferation. Previous studies have shown that gating of Orai1 channels is regulated by the outer pore residues V102 and F99, which together function as a hydrophobic gate to block ion conduction in resting channels. Opening of this gate occurs through a conformational change that moves F99 away from the permeation pathway, leading to pore hydration and ion conduction. In addition to this outer hydrophobic gate, several studies have postulated the presence of an inner gate formed by the basic residues R91, K87, and R83 in the inner pore. These positively charged residues were suggested to block ion conduction in closed channels via mechanisms involving either electrostatic repulsion or steric occlusion by a bound anion plug. However, in contrast to this model, here we find that neutralization of the basic residues dose-dependently abolishes both STIM1-mediated and STIM1-independent activation of Orai1 channels. Molecular dynamics simulations show that loss of the basic residues dehydrates the pore around the hydrophobic gate and stabilizes the pore in a closed configuration. Likewise, the severe combined immunodeficiency mutation, Orai1 R91W, closes the channel by dewetting the hydrophobic stretch of the pore and stabilizing F99 in a pore-facing configuration. Loss of STIM1-gating in R91W and in the other basic residue mutants is rescued by a V102A mutation, which restores pore hydration at the hydrophobic gate to repermit ion conduction. These results indicate that the inner pore basic residues facilitate opening of the principal outer hydrophobic gate through a long-range effect involving hydration of the outer pore.},
 bibtype = {article},
 author = {Yamashita, M. and Ing, C.E. and Yeung, P.S.-W. and Maneshi, M.M. and Pomès, R. and Prakriya, M.},
 doi = {10.1085/JGP.201912397},
 journal = {Journal of General Physiology},
 number = {1}
}

© 2019 Yamashita et al. Store-operated Orai1 channels regulate a wide range of cellular functions from gene expression to cell proliferation. Previous studies have shown that gating of Orai1 channels is regulated by the outer pore residues V102 and F99, which together function as a hydrophobic gate to block ion conduction in resting channels. Opening of this gate occurs through a conformational change that moves F99 away from the permeation pathway, leading to pore hydration and ion conduction. In addition to this outer hydrophobic gate, several studies have postulated the presence of an inner gate formed by the basic residues R91, K87, and R83 in the inner pore. These positively charged residues were suggested to block ion conduction in closed channels via mechanisms involving either electrostatic repulsion or steric occlusion by a bound anion plug. However, in contrast to this model, here we find that neutralization of the basic residues dose-dependently abolishes both STIM1-mediated and STIM1-independent activation of Orai1 channels. Molecular dynamics simulations show that loss of the basic residues dehydrates the pore around the hydrophobic gate and stabilizes the pore in a closed configuration. Likewise, the severe combined immunodeficiency mutation, Orai1 R91W, closes the channel by dewetting the hydrophobic stretch of the pore and stabilizing F99 in a pore-facing configuration. Loss of STIM1-gating in R91W and in the other basic residue mutants is rescued by a V102A mutation, which restores pore hydration at the hydrophobic gate to repermit ion conduction. These results indicate that the inner pore basic residues facilitate opening of the principal outer hydrophobic gate through a long-range effect involving hydration of the outer pore.

@article{
 title = {Substrate-Based Allosteric Regulation of a Homodimeric Enzyme},
 type = {article},
 year = {2019},
 pages = {11540-11556},
 volume = {141},
 id = {1e0cf90b-7f59-3239-b03d-c657672b16ed},
 created = {2019-08-03T17:02:55.732Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2019-08-03T17:03:24.569Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Many enzymes operate through half-of-the sites reactivity wherein a single protomer is catalytically engaged at one time. In the case of the homodimeric enzyme, fluoroacetate dehalogenase, substrate binding triggers closing of a regulatory cap domain in the empty protomer, preventing substrate access to the remaining active site. However, the empty protomer serves a critical role by acquiring more disorder upon substrate binding, thereby entropically favoring the forward reaction. Empty protomer dynamics are also allosterically coupled to the bound protomer, driving conformational exchange at the active site and progress along the reaction coordinate. Here, we show that at high concentrations, a second substrate binds along the substrate-access channel of the occupied protomer, thereby dampening interprotomer dynamics and inhibiting catalysis. While a mutation (K152I) abrogates second site binding and removes inhibitory effects, it also precipitously lowers the maximum catalytic rate, implying a role for the allosteric pocket at low substrate concentrations, where only a single substrate engages the enzyme at one time. We show that this outer pocket first desolvates the substrate, whereupon it is deposited in the active site. Substrate binding to the active site then triggers the empty outer pocket to serve as an interprotomer allosteric conduit, enabling enhanced dynamics and sampling of activation states needed for catalysis. These allosteric networks and the ensuing changes resulting from second substrate binding are delineated using rigidity-based allosteric transmission theory and validated by nuclear magnetic resonance and functional studies. The results illustrate the role of dynamics along allosteric networks in facilitating function.},
 bibtype = {article},
 author = {Mehrabi, Pedram and Di Pietrantonio, Christopher and Kim, Tae Hun and Sljoka, Adnan and Taverner, Keith and Ing, Christopher and Kruglyak, Natasha and Pomès, Régis and Pai, Emil F. and Prosser, R. Scott},
 doi = {10.1021/jacs.9b03703},
 journal = {Journal of the American Chemical Society},
 number = {29}
}

Many enzymes operate through half-of-the sites reactivity wherein a single protomer is catalytically engaged at one time. In the case of the homodimeric enzyme, fluoroacetate dehalogenase, substrate binding triggers closing of a regulatory cap domain in the empty protomer, preventing substrate access to the remaining active site. However, the empty protomer serves a critical role by acquiring more disorder upon substrate binding, thereby entropically favoring the forward reaction. Empty protomer dynamics are also allosterically coupled to the bound protomer, driving conformational exchange at the active site and progress along the reaction coordinate. Here, we show that at high concentrations, a second substrate binds along the substrate-access channel of the occupied protomer, thereby dampening interprotomer dynamics and inhibiting catalysis. While a mutation (K152I) abrogates second site binding and removes inhibitory effects, it also precipitously lowers the maximum catalytic rate, implying a role for the allosteric pocket at low substrate concentrations, where only a single substrate engages the enzyme at one time. We show that this outer pocket first desolvates the substrate, whereupon it is deposited in the active site. Substrate binding to the active site then triggers the empty outer pocket to serve as an interprotomer allosteric conduit, enabling enhanced dynamics and sampling of activation states needed for catalysis. These allosteric networks and the ensuing changes resulting from second substrate binding are delineated using rigidity-based allosteric transmission theory and validated by nuclear magnetic resonance and functional studies. The results illustrate the role of dynamics along allosteric networks in facilitating function.

@article{
 title = {Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export},
 type = {article},
 year = {2019},
 volume = {10},
 websites = {http://dx.doi.org/10.1038/s41467-019-11425-0},
 publisher = {Springer US},
 id = {96f72dac-5f31-304f-ae76-29a8a7135d8a},
 created = {2019-09-20T05:03:50.753Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2019-09-20T05:04:00.013Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Heybrock, Saskia and Kanerva, Kristiina and Meng, Ying and Ing, Chris and Liang, Anna and Xiong, Zi-Jian and Weng, Xialian and Ah Kim, Young and Collins, Richard and Trimble, William and Pomès, Régis and Privé, Gilbert G. and Annaert, Wim and Schwake, Michael and Heeren, Joerg and Lüllmann-Rauch, Renate and Grinstein, Sergio and Ikonen, Elina and Saftig, Paul and Neculai, Dante},
 doi = {10.1038/s41467-019-11425-0},
 journal = {Nature Communications},
 number = {1}
}

@article{
 title = {Hydrophobic gasket mutation produces gating pore currents in closed human voltage-gated proton channels},
 type = {article},
 year = {2019},
 volume = {116},
 id = {835fae3e-a340-3ddd-a43d-8337c60f9b37},
 created = {2019-09-20T05:03:50.893Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2019-09-20T05:04:04.212Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Banh, Richard and Cherny, Vladimir V and Morgan, Deri and Musset, Boris and Thomas, Sarah and Kulleperuma, Kethika},
 doi = {10.1073/pnas.1905462116},
 journal = {Proceedings of the National Academy of Sciences},
 number = {38}
}

@article{
 title = {Structural basis for gating pore current in periodic paralysi},
 type = {article},
 year = {2018},
 volume = {557},
 id = {dc7d7f44-a322-3b6a-b984-30497c1187c8},
 created = {2018-06-08T17:39:28.182Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.182Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2018 Macmillan Publishers Ltd., part of Springer Nature. Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness 1,2 . They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Na v 1.4 or the calcium channel Ca v 1.1 1,2 . Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis 1,2 by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state 3,4 . Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis 5 owing to cation leak in both activated and inactivated states 6 . Here we present high-resolution structures of the model bacterial sodium channel Na v Ab with the analogous gating-charge mutations 7,8 , which have similar functional effects as in the human channels. The R2G and R3G mutations have no effect on the backbone structures of the voltage sensor, but they create an aqueous cavity near the hydrophobic constriction site that controls gating charge movement through the voltage sensor. The R3G mutation extends the extracellular aqueous cleft through the entire length of the activated voltage sensor, creating an aqueous path through the membrane. Conversely, molecular modelling shows that the R2G mutation creates a continuous aqueous path through the membrane only in the resting state. Crystal structures of Na v Ab(R2G) in complex with guanidinium define a potential drug target site. Molecular dynamics simulations illustrate the mechanism of Na + permeation through the mutant gating pore in concert with conformational fluctuations of the gating charge R4. Our results reveal pathogenic mechanisms of periodic paralysis at the atomic level and suggest designs of drugs that may prevent ionic leak and provide symptomatic relief from hypokalaemic and normokalaemic periodic paralysis.},
 bibtype = {article},
 author = {Jiang, D. and Gamal El-Din, T.M. and Ing, C. and Lu, P. and Pomès, R. and Zheng, N. and Catterall, W.A.},
 doi = {10.1038/s41586-018-0120-4},
 journal = {Nature},
 number = {7706}
}

© 2018 Macmillan Publishers Ltd., part of Springer Nature. Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness 1,2 . They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Na v 1.4 or the calcium channel Ca v 1.1 1,2 . Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis 1,2 by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state 3,4 . Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis 5 owing to cation leak in both activated and inactivated states 6 . Here we present high-resolution structures of the model bacterial sodium channel Na v Ab with the analogous gating-charge mutations 7,8 , which have similar functional effects as in the human channels. The R2G and R3G mutations have no effect on the backbone structures of the voltage sensor, but they create an aqueous cavity near the hydrophobic constriction site that controls gating charge movement through the voltage sensor. The R3G mutation extends the extracellular aqueous cleft through the entire length of the activated voltage sensor, creating an aqueous path through the membrane. Conversely, molecular modelling shows that the R2G mutation creates a continuous aqueous path through the membrane only in the resting state. Crystal structures of Na v Ab(R2G) in complex with guanidinium define a potential drug target site. Molecular dynamics simulations illustrate the mechanism of Na + permeation through the mutant gating pore in concert with conformational fluctuations of the gating charge R4. Our results reveal pathogenic mechanisms of periodic paralysis at the atomic level and suggest designs of drugs that may prevent ionic leak and provide symptomatic relief from hypokalaemic and normokalaemic periodic paralysis.

@article{
 title = {Solution NMR structure of yeast Rcf1, a protein involved in respiratory supercomplex formation},
 type = {article},
 year = {2018},
 keywords = {Bicelles,Charge zipper,Lipids,Membrane proteins,Mitochondria},
 volume = {115},
 id = {dd98d0ab-c7ee-3979-b0cf-9054aefa36d3},
 created = {2018-06-08T17:39:28.258Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.258Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2018 National Academy of Sciences. All Rights Reserved. The Saccharomyces cerevisiae respiratory supercomplex factor 1 (Rcf1) protein is located in the mitochondrial inner membrane where it is involved in formation of supercomplexes composed of respiratory complexes III and IV. We report the solution structure of Rcf1, which forms a dimer in dodecylphosphocholine (DPC) micelles, where each monomer consists of a bundle of five transmembrane (TM) helices and a short flexible soluble helix (SH). Three TM helices are unusually charged and provide the dimerization interface consisting of 10 putative salt bridges, defining a "charge zipper" motif. The dimer structure is supported by molecular dynamics (MD) simulations in DPC, although the simulations show a more dynamic dimer interface than the NMR data. Furthermore, CD and NMR data indicate that Rcf1 undergoes a structural change when reconstituted in liposomes, which is supported by MD data, suggesting that the dimer  structure is unstable in a planar membrane environment. Collectively, these data indicate a dynamic monomer-dimer equilibrium. Furthermore, the Rcf1 dimer interacts with cytochrome c, suggesting a role as an electron-transfer bridge between complexes III and IV. The Rcf1 structure will help in understanding its functional roles at a molecular level.},
 bibtype = {article},
 author = {Zhou, S. and Pettersson, P. and Huang, J. and Sjöholm, J. and Sjöstrand, D. and Pomès, R. and Högbom, M. and Brzezinski, P. and Mäler, L. and Ädelroth, P.},
 doi = {10.1073/pnas.1712061115},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {12}
}

© 2018 National Academy of Sciences. All Rights Reserved. The Saccharomyces cerevisiae respiratory supercomplex factor 1 (Rcf1) protein is located in the mitochondrial inner membrane where it is involved in formation of supercomplexes composed of respiratory complexes III and IV. We report the solution structure of Rcf1, which forms a dimer in dodecylphosphocholine (DPC) micelles, where each monomer consists of a bundle of five transmembrane (TM) helices and a short flexible soluble helix (SH). Three TM helices are unusually charged and provide the dimerization interface consisting of 10 putative salt bridges, defining a "charge zipper" motif. The dimer structure is supported by molecular dynamics (MD) simulations in DPC, although the simulations show a more dynamic dimer interface than the NMR data. Furthermore, CD and NMR data indicate that Rcf1 undergoes a structural change when reconstituted in liposomes, which is supported by MD data, suggesting that the dimer structure is unstable in a planar membrane environment. Collectively, these data indicate a dynamic monomer-dimer equilibrium. Furthermore, the Rcf1 dimer interacts with cytochrome c, suggesting a role as an electron-transfer bridge between complexes III and IV. The Rcf1 structure will help in understanding its functional roles at a molecular level.

@article{
 title = {Mechanistic insights into allosteric regulation of the A<inf>2A</inf>adenosine G protein-coupled receptor by physiological cations},
 type = {article},
 year = {2018},
 volume = {9},
 id = {efcafab9-6369-3433-9844-08970e7a1544},
 created = {2018-06-08T17:39:28.271Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.271Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2018 The Author(s). Cations play key roles in regulating G-protein-coupled receptors (GPCRs), although their mechanisms are poorly understood. Here, 19 F NMR is used to delineate the effects of cations on functional states of the adenosine A 2A GPCR. While Na + reinforces an inactive ensemble and a partial-agonist stabilized state, Ca 2+ and Mg 2+ shift the equilibrium toward active states. Positive allosteric effects of divalent cations are more pronounced with agonist and a G-protein-derived peptide. In cell membranes, divalent cations enhance both the affinity and fraction of the high affinity agonist-bound state. Molecular dynamics simulations suggest high concentrations of divalent cations bridge specific extracellular acidic residues, bringing TM5 and TM6 together at the extracellular surface and allosterically driving open the G-protein-binding cleft as shown by rigidity-transmission allostery theory. An understanding of cation allostery should enable the design of allosteric agents and enhance our understanding of GPCR regulation in the cellular milieu.},
 bibtype = {article},
 author = {Ye, L. and Neale, C. and Sljoka, A. and Lyda, B. and Pichugin, D. and Tsuchimura, N. and Larda, S.T. and Pomès, R. and García, A.E. and Ernst, O.P. and Sunahara, R.K. and Prosser, R.S.},
 doi = {10.1038/s41467-018-03314-9},
 journal = {Nature Communications},
 number = {1}
}

© 2018 The Author(s). Cations play key roles in regulating G-protein-coupled receptors (GPCRs), although their mechanisms are poorly understood. Here, 19 F NMR is used to delineate the effects of cations on functional states of the adenosine A 2A GPCR. While Na + reinforces an inactive ensemble and a partial-agonist stabilized state, Ca 2+ and Mg 2+ shift the equilibrium toward active states. Positive allosteric effects of divalent cations are more pronounced with agonist and a G-protein-derived peptide. In cell membranes, divalent cations enhance both the affinity and fraction of the high affinity agonist-bound state. Molecular dynamics simulations suggest high concentrations of divalent cations bridge specific extracellular acidic residues, bringing TM5 and TM6 together at the extracellular surface and allosterically driving open the G-protein-binding cleft as shown by rigidity-transmission allostery theory. An understanding of cation allostery should enable the design of allosteric agents and enhance our understanding of GPCR regulation in the cellular milieu.

@article{
 title = {Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating},
 type = {article},
 year = {2018},
 keywords = {CRAC channels,Calcium,Orai1,STIM1,Store-operated calcium entry},
 volume = {115},
 id = {01334900-bc08-3a60-b108-d07f4af05d2e},
 created = {2018-06-11T20:18:43.482Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-11T20:18:43.482Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2018 National Academy of Sciences. All rights reserved. Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca 2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1–4 whose perturbation activates Orai1 channels independently of STIM1. Cysteine accessibility analysis and molecular-dynamics simulations indicated that constitutive activation of the most robust variant, H134S, arises from a pore conformational change that opens a hydrophobic gate to augment pore hydration, similar to gating evoked by STIM1. Mutational analysis of this locus suggests that H134 acts as steric brake to stabilize the closed state of the channel. In addition, atomic packing analysis revealed distinct functional contacts between the TM1 pore helix and the surrounding TM2/3 helices, including one set mediated by a cluster of interdigitating hydrophobic residues and another by alternative ridges of polar and hydrophobic residues. Perturbing these contacts via mutagenesis destabilizes STIM1-mediated Orai1 channel gating, indicating that these bridges between TM1 and the surrounding TM2/3 ring are critical for conveying the gating signal to the pore. These findings help develop a framework for understanding the global conformational changes and allosteric interactions between topologically distinct domains that are essential for activation of Orai1 channels.},
 bibtype = {article},
 author = {Yeung, P.S.-W. and Yamashita, M. and Ing, C.E. and Pomès, R. and Freymann, D.M. and Prakriya, M.},
 doi = {10.1073/pnas.1718373115},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {22}
}

© 2018 National Academy of Sciences. All rights reserved. Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca 2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1–4 whose perturbation activates Orai1 channels independently of STIM1. Cysteine accessibility analysis and molecular-dynamics simulations indicated that constitutive activation of the most robust variant, H134S, arises from a pore conformational change that opens a hydrophobic gate to augment pore hydration, similar to gating evoked by STIM1. Mutational analysis of this locus suggests that H134 acts as steric brake to stabilize the closed state of the channel. In addition, atomic packing analysis revealed distinct functional contacts between the TM1 pore helix and the surrounding TM2/3 helices, including one set mediated by a cluster of interdigitating hydrophobic residues and another by alternative ridges of polar and hydrophobic residues. Perturbing these contacts via mutagenesis destabilizes STIM1-mediated Orai1 channel gating, indicating that these bridges between TM1 and the surrounding TM2/3 ring are critical for conveying the gating signal to the pore. These findings help develop a framework for understanding the global conformational changes and allosteric interactions between topologically distinct domains that are essential for activation of Orai1 channels.

@article{
 title = {Role of Liquid–Liquid Phase Separation in Assembly of Elastin and Other Extracellular Matrix Proteins},
 type = {article},
 year = {2018},
 keywords = {biomaterials,coacervation,intrinsically disordered proteins,silk-like proteins,tropoelastin},
 id = {a0f9d20f-254b-33ee-bdfb-b459ae915877},
 created = {2018-07-13T19:38:36.470Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-07-13T19:38:36.470Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2018 Elsevier Ltd Liquid–liquid phase separation resulting in formation of colloidal droplets has recently attracted attention as a mechanism for rapid and transient assembly of intracellular macromolecules into functional units. Phase separation also appears to be a widespread and evolutionarily ancient mechanism for organization of proteins of the extracellular matrix into fibrillar, polymeric assemblies. Elastin, which provides the physical properties of extensibility and elastic recoil to large arteries, lungs and other tissues, is the best-characterized extracellular matrix protein whose polymeric assembly is initiated by phase separation. Recent studies have provided an atomistic description of the conformational ensemble of elastin-like proteins, and have begun to uncover how the interplay of local secondary structure, hydrophobicity and conformational disorder govern the structure, assembly and function of elastin. Monomeric elastin is a non-polar, glycine-rich, low-complexity, modular protein that remains predominantly disordered even in the crosslinked polymeric state, consistent with its function as an entropic elastomer. Unlike intracellular phase separation, which is reversible, phase separation of elastin and other matrix proteins proceeds to stabilization and clustering of condensed phase droplets and subsequent molecular organization into fibrillar, supramolecular structures. Short β-sheets appear to mediate the interaction and organization of these phase-separated droplets and modulate the ultimate material properties of the matrix. Whether phase separation is intracellular or extracellular, reversible or network-forming, understanding the sequence determinants of such varied assembly behaviors and differential fates of the colloidal droplets will provide important insights into aberrant assembly with pathological consequences and elucidate fundamental principles for the rational design of biomimetic materials.},
 bibtype = {article},
 author = {Muiznieks, L.D. and Sharpe, S. and Pomès, R. and Keeley, F.W.},
 doi = {10.1016/j.jmb.2018.06.010},
 journal = {Journal of Molecular Biology}
}

© 2018 Elsevier Ltd Liquid–liquid phase separation resulting in formation of colloidal droplets has recently attracted attention as a mechanism for rapid and transient assembly of intracellular macromolecules into functional units. Phase separation also appears to be a widespread and evolutionarily ancient mechanism for organization of proteins of the extracellular matrix into fibrillar, polymeric assemblies. Elastin, which provides the physical properties of extensibility and elastic recoil to large arteries, lungs and other tissues, is the best-characterized extracellular matrix protein whose polymeric assembly is initiated by phase separation. Recent studies have provided an atomistic description of the conformational ensemble of elastin-like proteins, and have begun to uncover how the interplay of local secondary structure, hydrophobicity and conformational disorder govern the structure, assembly and function of elastin. Monomeric elastin is a non-polar, glycine-rich, low-complexity, modular protein that remains predominantly disordered even in the crosslinked polymeric state, consistent with its function as an entropic elastomer. Unlike intracellular phase separation, which is reversible, phase separation of elastin and other matrix proteins proceeds to stabilization and clustering of condensed phase droplets and subsequent molecular organization into fibrillar, supramolecular structures. Short β-sheets appear to mediate the interaction and organization of these phase-separated droplets and modulate the ultimate material properties of the matrix. Whether phase separation is intracellular or extracellular, reversible or network-forming, understanding the sequence determinants of such varied assembly behaviors and differential fates of the colloidal droplets will provide important insights into aberrant assembly with pathological consequences and elucidate fundamental principles for the rational design of biomimetic materials.

@misc{
 title = {Lipid interactions enhance activation and potentiation of cystic fibrosis transmembrane conductance regulator (CFTR)},
 type = {misc},
 year = {2018},
 source = {bioRxiv},
 id = {7f30375a-ce8f-3955-b08b-5497c83e956f},
 created = {2020-10-27T23:59:00.000Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2020-10-29T15:44:35.682Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. The recent cryo-electron microscopy structures of phosphorylated, ATP-bound CFTR in detergent micelles failed to reveal an open anion conduction pathway as expected on the basis of previous functional studies in biological membranes. We tested the hypothesis that interaction of CFTR with lipids is important for opening of its channel. Interestingly, molecular dynamics studies revealed that phospholipids associate with regions of CFTR proposed to contribute to its channel activity. More directly, we found that CFTR purified together with associated lipids using the amphipol: A8-35, exhibited higher rates of catalytic activity, channel activation and potentiation using ivacaftor, than did CFTR purified in detergent. Catalytic activity in CFTR detergent micelles was partially rescued by addition of phospholipids plus cholesterol, arguing that these lipids contribute directly to its modulation. In summary, these studies highlight the importance of lipids in regulated CFTR channel activation and potentiation.},
 bibtype = {misc},
 author = {Chin, S. and Ramjeesingh, M. and Hung, M. and Ereño-Oreba, J. and Ing, C. and Zeng, Z.W. and Cui, H. and Pomès, R. and Julien, J.-P. and Bear, C.E.},
 doi = {10.1101/495010}
}

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. The recent cryo-electron microscopy structures of phosphorylated, ATP-bound CFTR in detergent micelles failed to reveal an open anion conduction pathway as expected on the basis of previous functional studies in biological membranes. We tested the hypothesis that interaction of CFTR with lipids is important for opening of its channel. Interestingly, molecular dynamics studies revealed that phospholipids associate with regions of CFTR proposed to contribute to its channel activity. More directly, we found that CFTR purified together with associated lipids using the amphipol: A8-35, exhibited higher rates of catalytic activity, channel activation and potentiation using ivacaftor, than did CFTR purified in detergent. Catalytic activity in CFTR detergent micelles was partially rescued by addition of phospholipids plus cholesterol, arguing that these lipids contribute directly to its modulation. In summary, these studies highlight the importance of lipids in regulated CFTR channel activation and potentiation.

@article{
 title = {STIM1 activates CRAC channels through rotation of the pore helix to open a hydrophobic gate},
 type = {article},
 year = {2017},
 pages = {14512},
 volume = {8},
 websites = {http://www.nature.com/doifinder/10.1038/ncomms14512},
 id = {3e597a05-7023-3c91-8e7e-f083926c5fc5},
 created = {2017-02-21T17:59:39.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Store-operated Ca2+ release-activated Ca2+ (CRAC) channels constitute a major pathway for Ca2+ influx and mediate many essential signalling functions in animal cells, yet how they open remains elusive. Here, we investigate the gating mechanism of the human CRAC channel Orai1 by its activator, stromal interacting molecule 1 (STIM1). We find that two rings of pore-lining residues, V102 and F99, work together to form a hydrophobic gate. Mutations of these residues to polar amino acids produce channels with leaky gates that conduct ions in the resting state. STIM1-mediated channel activation occurs through rotation of the pore helix, which displaces the F99 residues away from the pore axis to increase pore hydration, allowing ions to flow through the V102-F99 hydrophobic band. Pore helix rotation by STIM1 also explains the dynamic coupling between CRAC channel gating and ion selectivity. This hydrophobic gating mechanism has implications for CRAC channel function, pharmacology and disease-causing mutations.},
 bibtype = {article},
 author = {Yamashita, Megumi and Yeung, Priscilla S.-W. and Ing, Christopher E. and McNally, Beth A. and Pomès, Régis and Prakriya, Murali},
 doi = {10.1038/ncomms14512},
 journal = {Nature Communications}
}

Store-operated Ca2+ release-activated Ca2+ (CRAC) channels constitute a major pathway for Ca2+ influx and mediate many essential signalling functions in animal cells, yet how they open remains elusive. Here, we investigate the gating mechanism of the human CRAC channel Orai1 by its activator, stromal interacting molecule 1 (STIM1). We find that two rings of pore-lining residues, V102 and F99, work together to form a hydrophobic gate. Mutations of these residues to polar amino acids produce channels with leaky gates that conduct ions in the resting state. STIM1-mediated channel activation occurs through rotation of the pore helix, which displaces the F99 residues away from the pore axis to increase pore hydration, allowing ions to flow through the V102-F99 hydrophobic band. Pore helix rotation by STIM1 also explains the dynamic coupling between CRAC channel gating and ion selectivity. This hydrophobic gating mechanism has implications for CRAC channel function, pharmacology and disease-causing mutations.

@article{
 title = {The role of dimer asymmetry and protomer dynamics in enzyme catalysis},
 type = {article},
 year = {2017},
 pages = {eaag2355},
 volume = {355},
 websites = {http://www.sciencemag.org/lookup/doi/10.1126/science.aag2355},
 id = {997b3bae-fb81-3a8b-80a5-660e15824ff9},
 created = {2017-02-21T17:59:39.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Freeze-trapping x-ray crystallography, nuclear magnetic resonance, and computational techniques reveal the distribution of states and their interconversion rates along the reaction pathway of a bacterial homodimeric enzyme, fluoroacetate dehalogenase (FAcD). The crystal structure of apo-FAcD exhibits asymmetry around the dimer interface and cap domain, priming one protomer for substrate binding. This asymmetry is dynamically averaged through conformational exchange on a millisecond time scale. During catalysis, the protomer conformational exchange rate becomes enhanced, the empty protomer exhibits increased local disorder, and water egresses. Computational studies identify allosteric pathways between protomers. Water release and enhanced dynamics associated with catalysis compensate for entropic losses from substrate binding while facilitating sampling of the transition state. The studies provide insights into how substrate-coupled allosteric modulation of structure and dynamics facilitates catalysis in a homodimeric enzyme.},
 bibtype = {article},
 author = {Kim, Tae Hun and Mehrabi, Pedram and Ren, Zhong and Sljoka, Adnan and Ing, Christopher and Bezginov, Alexandr and Ye, Libin and Pomès, Régis and Prosser, R. Scott and Pai, Emil F.},
 doi = {10.1126/science.aag2355},
 journal = {Science},
 number = {6322}
}

Freeze-trapping x-ray crystallography, nuclear magnetic resonance, and computational techniques reveal the distribution of states and their interconversion rates along the reaction pathway of a bacterial homodimeric enzyme, fluoroacetate dehalogenase (FAcD). The crystal structure of apo-FAcD exhibits asymmetry around the dimer interface and cap domain, priming one protomer for substrate binding. This asymmetry is dynamically averaged through conformational exchange on a millisecond time scale. During catalysis, the protomer conformational exchange rate becomes enhanced, the empty protomer exhibits increased local disorder, and water egresses. Computational studies identify allosteric pathways between protomers. Water release and enhanced dynamics associated with catalysis compensate for entropic losses from substrate binding while facilitating sampling of the transition state. The studies provide insights into how substrate-coupled allosteric modulation of structure and dynamics facilitates catalysis in a homodimeric enzyme.

@article{
 title = {Orkambi ® and amplifier co-therapy improves function from a rare CFTR mutation in gene-edited cells and patient tissue},
 type = {article},
 year = {2017},
 keywords = {3700 a,amplifier,c,cas 9,cftr,crispr,cystic fibrosis,g,gene therapy,genetic disease,respiratory,subject categories genetics},
 pages = {1-20},
 id = {9b79cfe0-ed99-3ca4-91f5-f879158cac03},
 created = {2017-07-08T04:36:12.907Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-07-08T04:38:34.228Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The combination therapy of lumacaftor and ivacaftor (Orkambi®) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 It has been predicted that Orkambi® could treat patients with rarer mutations of similar "theratype"; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function-similar to ΔF508-CFTR, are unlikely to yield a robust Orkambi® response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient-derived tissue. A CRISPR/Cas9-edited bronchial epithelial cell line bearing this mutation enabled studies showing that an "amplifier" compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi® response. Importantly, this "amplifier" effect was recapitulated in patient-derived nasal cultures-providing the first evidence for its efficacy in augmenting Orkambi® in tissues harboring a rare CF-causing mutation. We propose that this multi-disciplinary approach, including creation of CRISPR/Cas9-edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations.},
 bibtype = {article},
 author = {Molinski, Steven V and Ahmadi, Saumel and Ip, Wan and Ouyang, Hong and Villella, Adriana and Miller, John P and Lee, Po-shun and Kulleperuma, Kethika and Du, Kai and Paola, Michelle Di and Eckford, Paul D W and Laselva, Onofrio and Huan, Ling Jun and Wellhauser, Leigh and Li, Ellen and Ray, Peter N and Pomès, Régis and Moraes, Theo J and Gonska, Tanja and Ratjen, Felix and Bear, Christine E},
 doi = {10.15252/emmm.201607137},
 journal = {EMBO Molecular Medicine}
}

The combination therapy of lumacaftor and ivacaftor (Orkambi®) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508 It has been predicted that Orkambi® could treat patients with rarer mutations of similar "theratype"; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function-similar to ΔF508-CFTR, are unlikely to yield a robust Orkambi® response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient-derived tissue. A CRISPR/Cas9-edited bronchial epithelial cell line bearing this mutation enabled studies showing that an "amplifier" compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi® response. Importantly, this "amplifier" effect was recapitulated in patient-derived nasal cultures-providing the first evidence for its efficacy in augmenting Orkambi® in tissues harboring a rare CF-causing mutation. We propose that this multi-disciplinary approach, including creation of CRISPR/Cas9-edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations.

@article{
 title = {Structures of closed and open states of a voltage-gated sodium channel},
 type = {article},
 year = {2017},
 pages = {201700761},
 websites = {http://www.pnas.org/lookup/doi/10.1073/pnas.1700761114},
 id = {4ac71a80-f5b7-3bd9-8abc-024588502cc3},
 created = {2017-07-08T04:38:54.114Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-07-08T04:40:25.051Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Bacterial voltage-gated sodium channels (BacNavs) serve as models of their vertebrate counterparts. BacNavs contain conserved voltage-sensing and pore-forming domains, but they are homotetramers of four identical subunits, rather than pseudotetramers of four homologous domains. Here, we present structures of two NaVAb mutants that capture tightly closed and open states at a resolution of 2.8-3.2 Å. Introduction of two humanizing mutations in the S6 segment (NaVAb/FY: T206F and V213Y) generates a persistently closed form of the activation gate in which the intracellular ends of the four S6 segments are drawn tightly together to block ion permeation completely. This construct also revealed the complete structure of the four-helix bundle that forms the C-terminal domain. In contrast, truncation of the C-terminal 40 residues in NavAb/1-226 captures the activation gate in an open conformation, revealing the open state of a BacNav with intact voltage sensors. Comparing these structures illustrates the full range of motion of the activation gate, from closed with its orifice fully occluded to open with an orifice of ∼10 Å. Molecular dynamics and free-energy simulations confirm designation of NaVAb/1-226 as an open state that allows permeation of hydrated Na(+), and these results also support a hydrophobic gating mechanism for control of ion permeation. These two structures allow completion of a closed-open-inactivated conformational cycle in a single voltage-gated sodium channel and give insight into the structural basis for state-dependent binding of sodium channel-blocking drugs.},
 bibtype = {article},
 author = {Lenaeus, Michael J. and Gamal El-Din, Tamer M. and Ing, Christopher and Ramanadane, Karthik and Pomès, Régis and Zheng, Ning and Catterall, William A.},
 doi = {10.1073/pnas.1700761114},
 journal = {Proceedings of the National Academy of Sciences}
}

Bacterial voltage-gated sodium channels (BacNavs) serve as models of their vertebrate counterparts. BacNavs contain conserved voltage-sensing and pore-forming domains, but they are homotetramers of four identical subunits, rather than pseudotetramers of four homologous domains. Here, we present structures of two NaVAb mutants that capture tightly closed and open states at a resolution of 2.8-3.2 Å. Introduction of two humanizing mutations in the S6 segment (NaVAb/FY: T206F and V213Y) generates a persistently closed form of the activation gate in which the intracellular ends of the four S6 segments are drawn tightly together to block ion permeation completely. This construct also revealed the complete structure of the four-helix bundle that forms the C-terminal domain. In contrast, truncation of the C-terminal 40 residues in NavAb/1-226 captures the activation gate in an open conformation, revealing the open state of a BacNav with intact voltage sensors. Comparing these structures illustrates the full range of motion of the activation gate, from closed with its orifice fully occluded to open with an orifice of ∼10 Å. Molecular dynamics and free-energy simulations confirm designation of NaVAb/1-226 as an open state that allows permeation of hydrated Na(+), and these results also support a hydrophobic gating mechanism for control of ion permeation. These two structures allow completion of a closed-open-inactivated conformational cycle in a single voltage-gated sodium channel and give insight into the structural basis for state-dependent binding of sodium channel-blocking drugs.

@article{
 title = {The liquid structure of elastin},
 type = {article},
 year = {2017},
 volume = {6},
 id = {662712f7-afaf-3d7e-ad96-b4ab3721ffa7},
 created = {2018-06-08T17:39:27.615Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.615Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© Rauscher and Pomès. The protein elastin imparts extensibility, elastic recoil, and resilience to tissues including arterial walls, skin, lung alveoli, and the uterus. Elastin and elastin-like peptides are hydrophobic, disordered, and undergo liquid-liquid phase separation upon self-assembly. Despite extensive study, the structure of elastin remains controversial. We use molecular dynamics simulations on a massive scale to elucidate the structural ensemble of aggregated elastin-like peptides. Consistent with the entropic nature of elastic recoil, the aggregated state is stabilized by the hydrophobic effect. However, self-assembly does not entail formation of a hydrophobic core. The polypeptide backbone forms transient, sparse hydrogen-bonded turns and remains significantly hydrated even as self-assembly triples the extent of non-polar side chain contacts. Individual chains in the assembly approach a maximally-disordered, melt-like state which may be called the liquid state of proteins. These findings resolve long-standing controversies regarding elastin structure and function and afford insight into the phase separation of disordered proteins.},
 bibtype = {article},
 author = {Rauscher, S. and Pomès, R.},
 doi = {10.7554/eLife.26526},
 journal = {eLife}
}

© Rauscher and Pomès. The protein elastin imparts extensibility, elastic recoil, and resilience to tissues including arterial walls, skin, lung alveoli, and the uterus. Elastin and elastin-like peptides are hydrophobic, disordered, and undergo liquid-liquid phase separation upon self-assembly. Despite extensive study, the structure of elastin remains controversial. We use molecular dynamics simulations on a massive scale to elucidate the structural ensemble of aggregated elastin-like peptides. Consistent with the entropic nature of elastic recoil, the aggregated state is stabilized by the hydrophobic effect. However, self-assembly does not entail formation of a hydrophobic core. The polypeptide backbone forms transient, sparse hydrogen-bonded turns and remains significantly hydrated even as self-assembly triples the extent of non-polar side chain contacts. Individual chains in the assembly approach a maximally-disordered, melt-like state which may be called the liquid state of proteins. These findings resolve long-standing controversies regarding elastin structure and function and afford insight into the phase separation of disordered proteins.

@article{
 title = {Molecular recognition and packing frustration in a helical protein},
 type = {article},
 year = {2017},
 volume = {13},
 id = {8e9aff29-8ebe-3ac6-8a5c-1c75c60d908f},
 created = {2018-06-08T17:39:28.034Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.034Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2017 Huynh et al. Biomolecular recognition entails attractive forces for the functional native states and discrimination against potential nonnative interactions that favor alternate stable configurations. The challenge posed by the competition of nonnative stabilization against native-centric forces is conceptualized as frustration. Experiment indicates that frustration is often minimal in evolved biological systems although nonnative possibilities are intuitively abundant. Much of the physical basis of minimal frustration in protein folding thus remains to be elucidated. Here we make progress by studying the colicin immunity protein Im9. To assess the energetic favorability of nonnative versus native interactions, we compute free energies of association of various combinations of the four helices in Im9 (referred to as H1, H2, H3, and H4) by extensive explicit-water molecular dynamics simulations (total simulated time  >  300 μs), focusing primarily on the pairs with the largest native contact surfaces, H1-H2 and H1-H4. Frustration is detected in H1-H2 packing in that a nonnative packing orientation is significantly stabilized relative to native, whereas such a prominent nonnative effect is not observed for H1-H4 packing. However, in contrast to the favored nonnative H1-H2 packing in isolation, the native H1-H2 packing orientation is stabilized by H3 and loop residues surrounding H4. Taken together, these results showcase the contextual nature of molecular recognition, and suggest further that nonnative effects in H1-H2 packing may be largely avoided by the experimentally inferred Im9 folding transition state with native packing most developed at the H1-H4 rather than the H1-H2 interface.},
 bibtype = {article},
 author = {Huynh, L. and Neale, C. and Pomès, R. and Chan, H.S.},
 doi = {10.1371/journal.pcbi.1005909},
 journal = {PLoS Computational Biology},
 number = {12}
}

© 2017 Huynh et al. Biomolecular recognition entails attractive forces for the functional native states and discrimination against potential nonnative interactions that favor alternate stable configurations. The challenge posed by the competition of nonnative stabilization against native-centric forces is conceptualized as frustration. Experiment indicates that frustration is often minimal in evolved biological systems although nonnative possibilities are intuitively abundant. Much of the physical basis of minimal frustration in protein folding thus remains to be elucidated. Here we make progress by studying the colicin immunity protein Im9. To assess the energetic favorability of nonnative versus native interactions, we compute free energies of association of various combinations of the four helices in Im9 (referred to as H1, H2, H3, and H4) by extensive explicit-water molecular dynamics simulations (total simulated time > 300 μs), focusing primarily on the pairs with the largest native contact surfaces, H1-H2 and H1-H4. Frustration is detected in H1-H2 packing in that a nonnative packing orientation is significantly stabilized relative to native, whereas such a prominent nonnative effect is not observed for H1-H4 packing. However, in contrast to the favored nonnative H1-H2 packing in isolation, the native H1-H2 packing orientation is stabilized by H3 and loop residues surrounding H4. Taken together, these results showcase the contextual nature of molecular recognition, and suggest further that nonnative effects in H1-H2 packing may be largely avoided by the experimentally inferred Im9 folding transition state with native packing most developed at the H1-H4 rather than the H1-H2 interface.

@article{
 title = {Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers},
 type = {article},
 year = {2017},
 volume = {6},
 id = {8ff5f184-8461-3f0f-bcda-23c70bc77e1f},
 created = {2018-06-08T17:39:28.344Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.344Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2017. Verasztó et al. The amyloid β peptide (Aβ) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aβ1-42 (oAβ1-42) and/or monomeric Aβ1-42 (mAβ1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAβ1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Aβ1-42. The presence of SST14 inhibited Aβ aggregation and masked the ability of several antibodies to detect Aβ. Notably, Aβ1-42, but not Aβ1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Ab- directed diagnostics and may signify a role of SST14 in the etiology of AD.},
 bibtype = {article},
 author = {Wang, H. and Muiznieks, L.D. and Ghosh, P. and Williams, D. and Solarski, M. and Fang, A. and Ruiz-Riquelme, A. and Pomès, R. and Watts, J.C. and Chakrabartty, A. and Wille, H. and Sharpe, S. and Schmitt-Ulms, G.},
 doi = {10.7554/eLife.28401},
 journal = {eLife}
}

© 2017. Verasztó et al. The amyloid β peptide (Aβ) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aβ1-42 (oAβ1-42) and/or monomeric Aβ1-42 (mAβ1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAβ1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Aβ1-42. The presence of SST14 inhibited Aβ aggregation and masked the ability of several antibodies to detect Aβ. Notably, Aβ1-42, but not Aβ1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Ab- directed diagnostics and may signify a role of SST14 in the etiology of AD.

@article{
 title = {Mechanism of Amyloidogenesis of a Bacterial AAA+ Chaperone},
 type = {article},
 year = {2016},
 pages = {1095-1109},
 websites = {http://linkinghub.elsevier.com/retrieve/pii/S0969212616300806},
 id = {946af7ff-b090-390a-8544-b9d31e2637f7},
 created = {2016-09-12T16:10:18.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Chan, Sze Wah Samuel and Yau, Jason and Ing, Christopher and Liu, Kaiyin and Farber, Patrick and Won, Amy and Bhandari, Vaibhav and Kara-Yacoubian, Nareg and Seraphim, Thiago V. and Chakrabarti, Nilmadhab and Kay, Lewis E. and Yip, Christopher M. and Pomès, Régis and Sharpe, Simon and Houry, Walid A.},
 doi = {10.1016/j.str.2016.05.002},
 journal = {Structure}
}

@article{
 title = {Atomistic Picture of Conformational Exchange in a T4 Lysozyme Cavity Mutant: An Experiment-Guided Molecular Dynamics Study},
 type = {article},
 year = {2016},
 pages = {3602-3613},
 volume = {3},
 id = {e6e09b22-aa51-346b-83c6-3783620e2aa7},
 created = {2016-09-12T16:10:18.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Despite the importance of dynamics to protein function there is little information about the states that are formed as the protein explores its conformational landscape or about the mechanism by which transitions between the different states occur. Here we used a combined NMR spin relaxation and unbiased molecular dynamics (MD) approach to investigate the exchange process by which a cavity in an L99A mutant of T4 lysozyme (T4L 99A) interconverts between an empty and occupied form that involves repositioning of an aromatic residue, Phe114. Although structures of the end-states of the exchange process are available, insight into the mechanism by which the transition takes place cannot be obtained from experiment and the timescales involved are too slow to address using brute force MD. Using spin relaxation NMR methods, we have identified a triple-mutant of T4L that undergoes the same exchange process as T4L L99A but where the minor state lifetime has decreased significantly so that the spontaneous conformational transition to the major state can be studied using all-atom MD simulations. The simulation trajectories were analyzed using Markov state models and the energy landscape so obtained is in good agreement with expectations based on NMR studies. Notably there is no large-scale perturbation of the structure during the transition, multiple intermediates are formed between the two similar exchanging conformations and the free energy barrier between these two well-folded, compact forms is small (6 kBT), only slightly larger than for processes considered to be barrierless.},
 bibtype = {article},
 author = {Vallurupalli, Pramodh and Chakrabarti, Nilmadhab and Pomes, Regis and Kay, Lewis},
 doi = {10.1039/C5SC03886C},
 journal = {Chemical Science}
}

Despite the importance of dynamics to protein function there is little information about the states that are formed as the protein explores its conformational landscape or about the mechanism by which transitions between the different states occur. Here we used a combined NMR spin relaxation and unbiased molecular dynamics (MD) approach to investigate the exchange process by which a cavity in an L99A mutant of T4 lysozyme (T4L 99A) interconverts between an empty and occupied form that involves repositioning of an aromatic residue, Phe114. Although structures of the end-states of the exchange process are available, insight into the mechanism by which the transition takes place cannot be obtained from experiment and the timescales involved are too slow to address using brute force MD. Using spin relaxation NMR methods, we have identified a triple-mutant of T4L that undergoes the same exchange process as T4L L99A but where the minor state lifetime has decreased significantly so that the spontaneous conformational transition to the major state can be studied using all-atom MD simulations. The simulation trajectories were analyzed using Markov state models and the energy landscape so obtained is in good agreement with expectations based on NMR studies. Notably there is no large-scale perturbation of the structure during the transition, multiple intermediates are formed between the two similar exchanging conformations and the free energy barrier between these two well-folded, compact forms is small (6 kBT), only slightly larger than for processes considered to be barrierless.

@article{
 title = {Structure of Human Acid Sphingomyelinase Reveals the Role of the Saposin Domain in Activating Substrate Hydrolysis},
 type = {article},
 year = {2016},
 pages = {3026-3042},
 websites = {http://linkinghub.elsevier.com/retrieve/pii/S0022283616302200},
 id = {5f0a65ea-1d94-3d79-b3b9-ce76f0867f02},
 created = {2016-09-12T16:10:18.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Xiong, Zi-Jian and Huang, Jingjing and Poda, Gennady and Pomès, Régis and Privé, Gilbert G.},
 doi = {10.1016/j.jmb.2016.06.012},
 journal = {Journal of Molecular Biology}
}

@article{
 title = {Sampling errors in free energy simulations of small molecules in lipid bilayers.},
 type = {article},
 year = {2016},
 keywords = {Free energy,Hidden barrier,Orthogonal barrier,PMF,Potential of mean force,Review,Simulation,US,Umbrella sampling},
 pages = {2539-2548},
 volume = {1858},
 websites = {http://www.sciencedirect.com/science/article/pii/S0005273616300839},
 publisher = {Elsevier B.V.},
 id = {5812e3ef-6fa4-38cb-b50a-205c76bc85ea},
 created = {2016-09-12T16:10:18.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Free energy simulations are a powerful tool for evaluating the interactions of molecular solutes with lipid bilayers as mimetics of cellular membranes. However, these simulations are frequently hindered by systematic sampling errors. This review highlights recent progress in computing free energy profiles for inserting molecular solutes into lipid bilayers. Particular emphasis is placed on a systematic analysis of the free energy profiles, identifying the sources of sampling errors that reduce computational efficiency, and highlighting methodological advances that may alleviate sampling deficiencies. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg.},
 bibtype = {article},
 author = {Neale, Chris and Pomès, Régis},
 doi = {10.1016/j.bbamem.2016.03.006},
 journal = {Biochimica et biophysica acta},
 number = {10}
}

Free energy simulations are a powerful tool for evaluating the interactions of molecular solutes with lipid bilayers as mimetics of cellular membranes. However, these simulations are frequently hindered by systematic sampling errors. This review highlights recent progress in computing free energy profiles for inserting molecular solutes into lipid bilayers. Particular emphasis is placed on a systematic analysis of the free energy profiles, identifying the sources of sampling errors that reduce computational efficiency, and highlighting methodological advances that may alleviate sampling deficiencies. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg.

@article{
 title = {Peptide Bond Isomerization in High-Temperature Simulations},
 type = {article},
 year = {2016},
 pages = {1989-1999},
 volume = {12},
 id = {8aac448f-1c06-3734-8a80-4e37816b455b},
 created = {2016-09-12T16:10:18.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Force fields for molecular simulation are generally optimized to model macromolecules such as proteins at ambient temperature and pressure. Nevertheless, elevated temperatures are frequently used to enhance conformational sampling, either during system setup or as a component of an advanced sampling technique such as temperature replica exchange. Because macromolecular force fields are now put upon to simulate temperatures and timescales that greatly exceed their original design specifications, it is appropriate to reevaluate whether these force fields are up to the task. Here, we quantify the rates of peptide bond isomerization in high-temperature simulations of three octameric peptides and a small fast-folding protein. We show that peptide octamers with and without proline residues undergo cis/trans isomerization every 1-5 nanoseconds at 800 K with three classical atomistic force fields (AMBER99SB-ILDN, CHARMM22/CMAP, and OPLS-AA/L). On the low microsecond timescale, these force fields permit isomerization of non-prolyl peptide bonds at temperatures ≥500 K and the CHARMM22/CMAP force field permits isomerizatino on prolyl peptide bonds ≥400 K. Moreover, the OPLS-AA/L force field allows chiral inversion about the Cα atom at 800 K. Finally, we show that temperature replica exchange permits cis peptide bonds developed at 540 K to subsequently migrate back to the 300 K ensemble, where cis peptide bonds are present in 2 ± 1 % of the population of Trp-cage TC5b, including up to 4 % of its folded state. Further work is required to assess the accuracy of cis/trans isomerization in the current generation of protein force fields.},
 bibtype = {article},
 author = {Neale, Chris and Pomès, Régis and Garcia, Angel E.},
 doi = {10.1021/acs.jctc.5b01022},
 journal = {Journal of Chemical Theory and Computation},
 number = {4}
}

Force fields for molecular simulation are generally optimized to model macromolecules such as proteins at ambient temperature and pressure. Nevertheless, elevated temperatures are frequently used to enhance conformational sampling, either during system setup or as a component of an advanced sampling technique such as temperature replica exchange. Because macromolecular force fields are now put upon to simulate temperatures and timescales that greatly exceed their original design specifications, it is appropriate to reevaluate whether these force fields are up to the task. Here, we quantify the rates of peptide bond isomerization in high-temperature simulations of three octameric peptides and a small fast-folding protein. We show that peptide octamers with and without proline residues undergo cis/trans isomerization every 1-5 nanoseconds at 800 K with three classical atomistic force fields (AMBER99SB-ILDN, CHARMM22/CMAP, and OPLS-AA/L). On the low microsecond timescale, these force fields permit isomerization of non-prolyl peptide bonds at temperatures ≥500 K and the CHARMM22/CMAP force field permits isomerizatino on prolyl peptide bonds ≥400 K. Moreover, the OPLS-AA/L force field allows chiral inversion about the Cα atom at 800 K. Finally, we show that temperature replica exchange permits cis peptide bonds developed at 540 K to subsequently migrate back to the 300 K ensemble, where cis peptide bonds are present in 2 ± 1 % of the population of Trp-cage TC5b, including up to 4 % of its folded state. Further work is required to assess the accuracy of cis/trans isomerization in the current generation of protein force fields.

@article{
 title = {Structure and Dynamics of Extracellular Loops in Human Aquaporin-1 from Solid-State NMR and Molecular Dynamics},
 type = {article},
 year = {2016},
 pages = {acs.jpcb.6b06731},
 websites = {http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.6b06731},
 id = {825a81b0-3455-3e6c-8f5d-8d78ac031db7},
 created = {2016-09-13T20:59:05.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Wang, Shenlin and Ing, Christopher and Emami, Sanaz and Jiang, Yunjiang and Liang, Hongjun and Pomès, Régis and Brown, Leonid S. and Ladizhansky, Vladimir},
 doi = {10.1021/acs.jpcb.6b06731},
 journal = {The Journal of Physical Chemistry B}
}

@book{
 title = {Simulation Studies of Ion Permeation and Selectivity in Voltage-Gated Sodium Channels},
 type = {book},
 year = {2016},
 source = {Current Topics in Membranes},
 keywords = {Computer simulation,Ion channels,Ion conduction,Ion permeation,Membrane proteins,Molecular dynamics,Potassium channels,Selectivity,Sodium channels,Voltage-gated sodium channel},
 volume = {78},
 id = {103df228-2767-3f8a-a5ed-1b006fab6538},
 created = {2018-06-08T17:39:27.472Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.472Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2016 Elsevier Inc. Voltage-gated ion channels are responsible for the generation and propagation of action potentials in electrically excitable cells. Molecular dynamics simulations have become a useful tool to study the molecular basis of ion transport in atomistic models of voltage-gated ion channels. The elucidation of several three-dimensional structures of bacterial voltage-gated sodium channels (Nav) in 2011 and 2012 opened the way to detailed computational investigations of this important class of membrane proteins. Here we review the numerous simulation studies of Na + permeation and selectivity in bacterial Nav channels published in the past 5 years. These studies use a variety of simulation methodologies differing in force field parameters, molecular models, sampling algorithms, and simulation times. Although results disagree on the details of ion permeation mechanisms, they concur in the presence of two primary Na + binding sites in the selectivity filter and support a loosely coupled knock-on mechanism of Na + permeation. Comparative studies of Na + , K + , and Ca 2+ permeation reveal sites within Nav channels that are Na + selective, yet a consensus model of selectivity has not been established. We discuss the agreement between simulation and experimental results and propose strategies that may be used to resolve discrepancies between simulation studies in order to improve future computational studies of permeation and selectivity in ion channels.},
 bibtype = {book},
 author = {Ing, C. and Pomès, R.},
 doi = {10.1016/bs.ctm.2016.07.005}
}

© 2016 Elsevier Inc. Voltage-gated ion channels are responsible for the generation and propagation of action potentials in electrically excitable cells. Molecular dynamics simulations have become a useful tool to study the molecular basis of ion transport in atomistic models of voltage-gated ion channels. The elucidation of several three-dimensional structures of bacterial voltage-gated sodium channels (Nav) in 2011 and 2012 opened the way to detailed computational investigations of this important class of membrane proteins. Here we review the numerous simulation studies of Na + permeation and selectivity in bacterial Nav channels published in the past 5 years. These studies use a variety of simulation methodologies differing in force field parameters, molecular models, sampling algorithms, and simulation times. Although results disagree on the details of ion permeation mechanisms, they concur in the presence of two primary Na + binding sites in the selectivity filter and support a loosely coupled knock-on mechanism of Na + permeation. Comparative studies of Na + , K + , and Ca 2+ permeation reveal sites within Nav channels that are Na + selective, yet a consensus model of selectivity has not been established. We discuss the agreement between simulation and experimental results and propose strategies that may be used to resolve discrepancies between simulation studies in order to improve future computational studies of permeation and selectivity in ion channels.

@article{
 title = {Atomistic picture of conformational exchange in a t4 lysozyme cavity mutant: An experiment-guided molecular dynamics study},
 type = {article},
 year = {2016},
 volume = {7},
 id = {7ae9d7e5-e063-344b-a237-48d934410cad},
 created = {2018-06-08T17:39:27.623Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.623Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© The Royal Society of Chemistry 2016. Despite the importance of dynamics to protein function there is little information about the states that are formed as the protein explores its conformational landscape or about the mechanism by which transitions between the different states occur. Here we used a combined NMR spin relaxation and unbiased molecular dynamics (MD) approach to investigate the exchange process by which a cavity in an L99A mutant of T4 lysozyme (T4L 99A) interconverts between an empty and occupied form that involves repositioning of an aromatic residue, Phe114. Although structures of the end-states of the exchange process are available, insight into the mechanism by which the transition takes place cannot be obtained from experiment and the timescales involved are too slow to address using brute force MD. Using spin relaxation NMR methods, we have identified a triple-mutant of T4L that undergoes the same exchange process as T4L L99A but where the minor state lifetime has decreased significantly so that the spontaneous conformational transition to the major state can be studied using all-atom MD simulations. The simulation trajectories were analyzed using Markov state models and the energy landscape so obtained is in good agreement with expectations based on NMR studies. Notably there is no large-scale perturbation of the structure during the transition, multiple intermediates are formed between the two similar exchanging conformations and the free energy barrier between these two well-folded, compact forms is small (6k B T), only slightly larger than for processes considered to be barrierless.},
 bibtype = {article},
 author = {Vallurupalli, P. and Chakrabarti, N. and Pomès, R. and Kay, L.E.},
 doi = {10.1039/c5sc03886c},
 journal = {Chemical Science},
 number = {6}
}

© The Royal Society of Chemistry 2016. Despite the importance of dynamics to protein function there is little information about the states that are formed as the protein explores its conformational landscape or about the mechanism by which transitions between the different states occur. Here we used a combined NMR spin relaxation and unbiased molecular dynamics (MD) approach to investigate the exchange process by which a cavity in an L99A mutant of T4 lysozyme (T4L 99A) interconverts between an empty and occupied form that involves repositioning of an aromatic residue, Phe114. Although structures of the end-states of the exchange process are available, insight into the mechanism by which the transition takes place cannot be obtained from experiment and the timescales involved are too slow to address using brute force MD. Using spin relaxation NMR methods, we have identified a triple-mutant of T4L that undergoes the same exchange process as T4L L99A but where the minor state lifetime has decreased significantly so that the spontaneous conformational transition to the major state can be studied using all-atom MD simulations. The simulation trajectories were analyzed using Markov state models and the energy landscape so obtained is in good agreement with expectations based on NMR studies. Notably there is no large-scale perturbation of the structure during the transition, multiple intermediates are formed between the two similar exchanging conformations and the free energy barrier between these two well-folded, compact forms is small (6k B T), only slightly larger than for processes considered to be barrierless.

@article{
 title = {Hydrophobic Gating of Ion Permeation in Magnesium Channel CorA},
 type = {article},
 year = {2015},
 pages = {e1004303},
 volume = {11},
 websites = {http://dx.plos.org/10.1371/journal.pcbi.1004303},
 id = {fea599c6-1ad5-3de1-962c-e204f8887328},
 created = {2015-07-16T19:45:10.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Ion channels catalyze ionic permeation across membranes via water-filled pores. To under- stand how changes in intracellular magnesium concentration regulate the influx of Mg2+ into cells, we examine early events in the relaxation of Mg2+ channel CorA toward its open state using massively-repeated molecular dynamics simulations conducted either with or without regulatory ions. The pore of CorA contains a 2-nm-long hydrophobic bottleneck which remained dehydrated in most simulations. However, rapid hydration or “wetting” events con- current with small-amplitude fluctuations in pore diameter occurred spontaneously and reversibly. In the absence of regulatory ions, wetting transitions are more likely and include a wet state that is significantly more stable and more hydrated. The free energy profile for Mg2+ permeation presents a barrier whose magnitude is anticorrelated to pore diameter and the extent of hydrophobic hydration. These findings support an allosteric mechanism whereby wetting of a hydrophobic gate couples changes in intracellular magnesium con- centration to the onset of ionic conduction.},
 bibtype = {article},
 author = {Neale, Chris and Chakrabarti, Nilmadhab and Pomorski, Pawel and Pai, Emil F. and Pomès, Régis},
 doi = {10.1371/journal.pcbi.1004303},
 journal = {PLOS Computational Biology},
 number = {7}
}

Ion channels catalyze ionic permeation across membranes via water-filled pores. To under- stand how changes in intracellular magnesium concentration regulate the influx of Mg2+ into cells, we examine early events in the relaxation of Mg2+ channel CorA toward its open state using massively-repeated molecular dynamics simulations conducted either with or without regulatory ions. The pore of CorA contains a 2-nm-long hydrophobic bottleneck which remained dehydrated in most simulations. However, rapid hydration or “wetting” events con- current with small-amplitude fluctuations in pore diameter occurred spontaneously and reversibly. In the absence of regulatory ions, wetting transitions are more likely and include a wet state that is significantly more stable and more hydrated. The free energy profile for Mg2+ permeation presents a barrier whose magnitude is anticorrelated to pore diameter and the extent of hydrophobic hydration. These findings support an allosteric mechanism whereby wetting of a hydrophobic gate couples changes in intracellular magnesium con- centration to the onset of ionic conduction.

@article{
 title = {Can Specific Protein-Lipid Interactions Stabilize an Active State of the Beta 2 Adrenergic Receptor?},
 type = {article},
 year = {2015},
 pages = {1652-1662},
 volume = {109},
 id = {2a916da8-70da-3f70-b74d-f83a06ede1d4},
 created = {2015-10-20T17:27:45.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {G-protein-coupled receptors are eukaryotic membrane proteins with broad biological and pharmacological rele- vance. Like all membrane-embedded proteins, their location and orientation are influenced by lipids, which can also impact pro- tein function via specific interactions. Extensive simulations totaling 0.25 ms reveal a process in which phospholipids from the membrane’s cytosolic leaflet enter the empty G-protein binding site of an activated b2 adrenergic receptor and form salt-bridge interactions that inhibit ionic lock formation and prolong active-state residency. Simulations of the receptor embedded in an anionic membrane show increased lipid binding, providing a molecular mechanism for the experimental observation that anionic lipids can enhance receptor activity. Conservation of the arginine component of the ionic lock among Rhodopsin-like G-protein- coupled receptors suggests that intracellular lipid ingression between receptor helices H6 and H7 may be a general mechanism for active-state stabilization.},
 bibtype = {article},
 author = {Neale, Chris and Herce, Henry D and Pomès, Régis and Garcia, Angel},
 doi = {10.1016/j.bpj.2015.08.028},
 journal = {Biophys. J.},
 number = {October}
}

G-protein-coupled receptors are eukaryotic membrane proteins with broad biological and pharmacological rele- vance. Like all membrane-embedded proteins, their location and orientation are influenced by lipids, which can also impact pro- tein function via specific interactions. Extensive simulations totaling 0.25 ms reveal a process in which phospholipids from the membrane’s cytosolic leaflet enter the empty G-protein binding site of an activated b2 adrenergic receptor and form salt-bridge interactions that inhibit ionic lock formation and prolong active-state residency. Simulations of the receptor embedded in an anionic membrane show increased lipid binding, providing a molecular mechanism for the experimental observation that anionic lipids can enhance receptor activity. Conservation of the arginine component of the ionic lock among Rhodopsin-like G-protein- coupled receptors suggests that intracellular lipid ingression between receptor helices H6 and H7 may be a general mechanism for active-state stabilization.

@article{
 title = {The molecular mechanism of Zinc acquisition by the neisserial outer-membrane transporter ZnuD},
 type = {article},
 year = {2015},
 pages = {7996},
 volume = {6},
 websites = {http://www.nature.com/doifinder/10.1038/ncomms8996},
 id = {1ec44a8e-0070-3976-8b80-e7154c66c02f},
 created = {2015-10-20T17:27:45.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Invading bacteria from the Neisseriaceae, Acinetobacteriaceae, Bordetellaceae and Moraxellaceae families express the conserved outer-membrane zinc transporter zinc-uptake component D (ZnuD) to overcome nutritional restriction imposed by the host organism during infection. Here we demonstrate that ZnuD is required for efficient systemic infections by the causative agent of bacterial meningitis, Neisseria meningitidis, in a mouse model. We also combine X-ray crystallography and molecular dynamics simulations to gain insight into the mechanism of zinc recognition and transport across the bacterial outer-membrane by ZnuD. Because ZnuD is also considered a promising vaccine candidate against N. meningitidis, we use several ZnuD structural intermediates to map potential antigenic epitopes, and propose a mechanism by which ZnuD can maintain high sequence conservation yet avoid immune recognition by altering the conformation of surface-exposed loops.},
 bibtype = {article},
 author = {Calmettes, Charles and Ing, Christopher and Buckwalter, Carolyn M. and El Bakkouri, Majida and Chieh-Lin Lai, Christine and Pogoutse, Anastassia and Gray-Owen, Scott D. and Pomès, Régis and Moraes, Trevor F.},
 doi = {10.1038/ncomms8996},
 journal = {Nature Communications}
}

Invading bacteria from the Neisseriaceae, Acinetobacteriaceae, Bordetellaceae and Moraxellaceae families express the conserved outer-membrane zinc transporter zinc-uptake component D (ZnuD) to overcome nutritional restriction imposed by the host organism during infection. Here we demonstrate that ZnuD is required for efficient systemic infections by the causative agent of bacterial meningitis, Neisseria meningitidis, in a mouse model. We also combine X-ray crystallography and molecular dynamics simulations to gain insight into the mechanism of zinc recognition and transport across the bacterial outer-membrane by ZnuD. Because ZnuD is also considered a promising vaccine candidate against N. meningitidis, we use several ZnuD structural intermediates to map potential antigenic epitopes, and propose a mechanism by which ZnuD can maintain high sequence conservation yet avoid immune recognition by altering the conformation of surface-exposed loops.

@article{
 title = {Indolicidin Binding Induces Thinning of a Lipid Bilayer},
 type = {article},
 year = {2014},
 pages = {L29-L31},
 volume = {106},
 websites = {http://linkinghub.elsevier.com/retrieve/pii/S0006349514002756},
 month = {4},
 id = {30091776-c604-37a9-98ee-78200f1ea353},
 created = {2014-04-15T19:01:47.000Z},
 accessed = {2014-04-15},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {We use all-atom molecular dynamics simulations on a massive scale to compute the standard binding free energy of the 13-residue antimicrobial peptide indolicidin to a lipid bilayer. The analysis of statistical convergence reveals systematic sampling errors that correlate with reorganization of the bilayer on the microsecond timescale and persist throughout a total of 1.4 ms of sampling. Consistent with experimental observations, indolicidin induces membrane thinning, although the simulations significantly overestimate the lipophilicity of the peptide.},
 bibtype = {article},
 author = {Neale, Chris and Hsu, Jenny C.Y. and Yip, Christopher M. and Pomès, Régis},
 doi = {10.1016/j.bpj.2014.02.031},
 journal = {Biophysical Journal},
 number = {8}
}

We use all-atom molecular dynamics simulations on a massive scale to compute the standard binding free energy of the 13-residue antimicrobial peptide indolicidin to a lipid bilayer. The analysis of statistical convergence reveals systematic sampling errors that correlate with reorganization of the bilayer on the microsecond timescale and persist throughout a total of 1.4 ms of sampling. Consistent with experimental observations, indolicidin induces membrane thinning, although the simulations significantly overestimate the lipophilicity of the peptide.

@article{
 title = {Modification and periplasmic translocation of the biofilm exopolysaccharide poly-β-1,6-N-acetyl-d-glucosamine.},
 type = {article},
 year = {2014},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/24994902},
 month = {7},
 day = {3},
 id = {050bca15-0168-37cb-bd9f-b3611a3c3640},
 created = {2014-07-26T19:38:54.000Z},
 accessed = {2014-07-10},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Poly-β-1,6-N-acetyl-d-glucosamine (PNAG) is an exopolysaccharide produced by a wide variety of medically important bacteria. Polyglucosamine subunit B (PgaB) is responsible for the de-N-acetylation of PNAG, a process required for polymer export and biofilm formation. PgaB is located in the periplasm and likely bridges the inner membrane synthesis and outer membrane export machinery. Here, we present structural, functional, and molecular simulation data that suggest PgaB associates with PNAG continuously during periplasmic transport. We show that the association of PgaB's N- and C-terminal domains forms a cleft required for the binding and de-N-acetylation of PNAG. Molecular dynamics (MD) simulations of PgaB show a binding preference for N-acetylglucosamine (GlcNAc) to the N-terminal domain and glucosammonium to the C-terminal domain. Continuous ligand binding density is observed that extends around PgaB from the N-terminal domain active site to an electronegative groove on the C-terminal domain that would allow for a processive mechanism. PgaB's C-terminal domain (PgaB310-672) directly binds PNAG oligomers with dissociation constants of ∼1-3 mM, and the structures of PgaB310-672 in complex with β-1,6-(GlcNAc)6, GlcNAc, and glucosamine reveal a unique binding mode suitable for interaction with de-N-acetylated PNAG (dPNAG). Furthermore, PgaB310-672 contains a β-hairpin loop (βHL) important for binding PNAG that was disordered in previous PgaB42-655 structures and is highly dynamic in the MD simulations. We propose that conformational changes in PgaB310-672 mediated by the βHL on binding of PNAG/dPNAG play an important role in the targeting of the polymer for export and its release.},
 bibtype = {article},
 author = {Little, Dustin J and Li, Grace and Ing, Christopher and DiFrancesco, Benjamin R and Bamford, Natalie C and Robinson, Howard and Nitz, Mark and Pomès, Régis and Howell, P Lynne},
 doi = {10.1073/pnas.1406388111},
 journal = {Proceedings of the National Academy of Sciences of the United States of America}
}

Poly-β-1,6-N-acetyl-d-glucosamine (PNAG) is an exopolysaccharide produced by a wide variety of medically important bacteria. Polyglucosamine subunit B (PgaB) is responsible for the de-N-acetylation of PNAG, a process required for polymer export and biofilm formation. PgaB is located in the periplasm and likely bridges the inner membrane synthesis and outer membrane export machinery. Here, we present structural, functional, and molecular simulation data that suggest PgaB associates with PNAG continuously during periplasmic transport. We show that the association of PgaB's N- and C-terminal domains forms a cleft required for the binding and de-N-acetylation of PNAG. Molecular dynamics (MD) simulations of PgaB show a binding preference for N-acetylglucosamine (GlcNAc) to the N-terminal domain and glucosammonium to the C-terminal domain. Continuous ligand binding density is observed that extends around PgaB from the N-terminal domain active site to an electronegative groove on the C-terminal domain that would allow for a processive mechanism. PgaB's C-terminal domain (PgaB310-672) directly binds PNAG oligomers with dissociation constants of ∼1-3 mM, and the structures of PgaB310-672 in complex with β-1,6-(GlcNAc)6, GlcNAc, and glucosamine reveal a unique binding mode suitable for interaction with de-N-acetylated PNAG (dPNAG). Furthermore, PgaB310-672 contains a β-hairpin loop (βHL) important for binding PNAG that was disordered in previous PgaB42-655 structures and is highly dynamic in the MD simulations. We propose that conformational changes in PgaB310-672 mediated by the βHL on binding of PNAG/dPNAG play an important role in the targeting of the polymer for export and its release.

@article{
 title = {The Conformational Ensemble of the β-Casein Phosphopeptide Reveals Two Independent Intrinsically Disordered Segments.},
 type = {article},
 year = {2014},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/25227946},
 month = {10},
 day = {2},
 id = {f2849a5a-1791-33a7-8a35-9509b3b0aaa7},
 created = {2014-10-03T02:39:35.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The β-casein phosphopeptide 1-25 (βCPP) is involved in calcium binding, cellular transduction, and dental remineralization. Though the net charge of 13e suggests an intrinsically disordered peptide, it has been shown to possibly maintain partial structure. To investigate the nature and extent of its conformational disorder, 100 independent molecular dynamics simulations (cumulative time of 30 μs) were conducted in explicit water with 0.1 M sodium chloride. βCPP adopted an ensemble of conformations (Rg = 8.61 ± 0.06 Å) stabilized primarily by ionic interactions and less so by hydrogen bonding (HB). Intramolecular contact maps showed a lack of interaction between the peptide's head (RELEELNVPGEIVEΣ) and tail (ΣΣΣEESITR) segments, suggesting their conformational independence. While many backbone HB interactions were observed between the amino acids in each segment, there was no persistent secondary structure evident. Our findings provide a framework for further investigation of βCPP's conformation and mechanism of action upon binding to calcium phosphate.},
 bibtype = {article},
 author = {Naqvi, Muhammad Ali and Rauscher, Sarah and Pomès, Régis and Rousseau, Dérick},
 doi = {10.1021/bi500107u},
 journal = {Biochemistry}
}

The β-casein phosphopeptide 1-25 (βCPP) is involved in calcium binding, cellular transduction, and dental remineralization. Though the net charge of 13e suggests an intrinsically disordered peptide, it has been shown to possibly maintain partial structure. To investigate the nature and extent of its conformational disorder, 100 independent molecular dynamics simulations (cumulative time of 30 μs) were conducted in explicit water with 0.1 M sodium chloride. βCPP adopted an ensemble of conformations (Rg = 8.61 ± 0.06 Å) stabilized primarily by ionic interactions and less so by hydrogen bonding (HB). Intramolecular contact maps showed a lack of interaction between the peptide's head (RELEELNVPGEIVEΣ) and tail (ΣΣΣEESITR) segments, suggesting their conformational independence. While many backbone HB interactions were observed between the amino acids in each segment, there was no persistent secondary structure evident. Our findings provide a framework for further investigation of βCPP's conformation and mechanism of action upon binding to calcium phosphate.

@article{
 title = {Modulated growth, stability and interactions of liquid-like coacervate assemblies of elastin},
 type = {article},
 year = {2014},
 keywords = {Colloid,Elastin,Interface,Phase separation,Self-assembly},
 volume = {36},
 id = {dbad3f94-1340-3568-baf8-9244a72952c1},
 created = {2018-06-08T17:39:28.103Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.103Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {© 2014. Elastin self-assembles from monomers into polymer networks that display elasticity and resilience. The first major step in assembly is a liquid-liquid phase separation known as coacervation. This process represents a continuum of stages from initial phase separation to early growth of droplets by coalescence and later "maturation" leading to fiber formation. Assembly of tropoelastin-rich globules is on pathway for fiber formation in vivo. However, little is known about these intermediates beyond their size distribution. Here we investigate the contribution of sequence and structural motifs from full-length tropoelastin and a set of elastin-like polypeptides to the maturation of coacervate assemblies, observing their growth, stability and interaction behavior, and polypeptide alignment within matured globules. We conclude that maturation is driven by surface properties, leading to stabilization of the interface between the hydrophobic interior and aqueous solvent, potentially through structural motifs, and discuss implications for droplet interactions in fiber formation.},
 bibtype = {article},
 author = {Muiznieks, L.D. and Cirulis, J.T. and van der Horst, A. and Reinhardt, D.P. and Wuite, G.J.L. and Pomès, R. and Keeley, F.W.},
 doi = {10.1016/j.matbio.2014.03.008},
 journal = {Matrix Biology}
}

© 2014. Elastin self-assembles from monomers into polymer networks that display elasticity and resilience. The first major step in assembly is a liquid-liquid phase separation known as coacervation. This process represents a continuum of stages from initial phase separation to early growth of droplets by coalescence and later "maturation" leading to fiber formation. Assembly of tropoelastin-rich globules is on pathway for fiber formation in vivo. However, little is known about these intermediates beyond their size distribution. Here we investigate the contribution of sequence and structural motifs from full-length tropoelastin and a set of elastin-like polypeptides to the maturation of coacervate assemblies, observing their growth, stability and interaction behavior, and polypeptide alignment within matured globules. We conclude that maturation is driven by surface properties, leading to stabilization of the interface between the hydrophobic interior and aqueous solvent, potentially through structural motifs, and discuss implications for droplet interactions in fiber formation.

@article{
 title = {Construction and validation of a homology model of the human voltage-gated proton channel hHV1},
 type = {article},
 year = {2013},
 pages = {445-465},
 volume = {141},
 websites = {http://www.jgp.org/cgi/doi/10.1085/jgp.201210856},
 month = {3},
 day = {25},
 id = {5bd81013-cdd4-3ecb-ba62-1dd8c138c044},
 created = {2013-03-25T20:21:29.000Z},
 accessed = {2013-03-25},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Kulleperuma, K. and Smith, S. M. E. and Morgan, D. and Musset, B. and Holyoake, J. and Chakrabarti, N. and Cherny, V. V. and DeCoursey, T. E. and Pomes, R.},
 doi = {10.1085/jgp.201210856},
 journal = {The Journal of General Physiology},
 number = {4}
}

@article{
 title = {Detergent-mediated protein aggregation.},
 type = {article},
 year = {2013},
 pages = {72-84},
 volume = {169},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23466535},
 month = {3},
 publisher = {Elsevier Ireland Ltd},
 day = {4},
 id = {0e42e281-ed49-3da3-a1d6-44823f249221},
 created = {2013-03-25T20:34:56.000Z},
 accessed = {2013-03-25},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Because detergents are commonly used to solvate membrane proteins for structural evaluation, much attention has been devoted to assessing the conformational bias imparted by detergent micelles in comparison to the native environment of the lipid bilayer. Here, we conduct six 500-ns simulations of a system with >600,000 atoms to investigate the spontaneous self assembly of dodecylphosphocholine detergent around multiple molecules of the integral membrane protein PagP. This detergent formed equatorial micelles in which acyl chains surround the protein's hydrophobic belt, confirming existing models of the detergent solvation of membrane proteins. In addition, unexpectedly, the extracellular and periplasmic apical surfaces of PagP interacted with the headgroups of detergents in other micelles 85 and 60% of the time, respectively, forming complexes that were stable for hundreds of nanoseconds. In some cases, an apical surface of one molecule of PagP interacted with an equatorial micelle surrounding another molecule of PagP. In other cases, the apical surfaces of two molecules of PagP simultaneously bound a neat detergent micelle. In these ways, detergents mediated the non-specific aggregation of folded PagP. These simulation results are consistent with dynamic light scattering experiments, which show that, at detergent concentrations ≥600mM, PagP induces the formation of large scattering species that are likely to contain many copies of the PagP protein. Together, these simulation and experimental results point to a potentially generic mechanism of detergent-mediated protein aggregation.},
 bibtype = {article},
 author = {Neale, Chris and Ghanei, Hamed and Holyoake, John and Bishop, Russell E and Privé, Gilbert G and Pomès, Régis},
 doi = {10.1016/j.chemphyslip.2013.02.005},
 journal = {Chemistry and physics of lipids}
}

Because detergents are commonly used to solvate membrane proteins for structural evaluation, much attention has been devoted to assessing the conformational bias imparted by detergent micelles in comparison to the native environment of the lipid bilayer. Here, we conduct six 500-ns simulations of a system with >600,000 atoms to investigate the spontaneous self assembly of dodecylphosphocholine detergent around multiple molecules of the integral membrane protein PagP. This detergent formed equatorial micelles in which acyl chains surround the protein's hydrophobic belt, confirming existing models of the detergent solvation of membrane proteins. In addition, unexpectedly, the extracellular and periplasmic apical surfaces of PagP interacted with the headgroups of detergents in other micelles 85 and 60% of the time, respectively, forming complexes that were stable for hundreds of nanoseconds. In some cases, an apical surface of one molecule of PagP interacted with an equatorial micelle surrounding another molecule of PagP. In other cases, the apical surfaces of two molecules of PagP simultaneously bound a neat detergent micelle. In these ways, detergents mediated the non-specific aggregation of folded PagP. These simulation results are consistent with dynamic light scattering experiments, which show that, at detergent concentrations ≥600mM, PagP induces the formation of large scattering species that are likely to contain many copies of the PagP protein. Together, these simulation and experimental results point to a potentially generic mechanism of detergent-mediated protein aggregation.

@article{
 title = {Binding Mechanism of Inositol Stereoisomers to Monomers and Aggregates of Aβ(16-22).},
 type = {article},
 year = {2013},
 pages = {6603–6613},
 volume = {117},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23627280},
 month = {5},
 day = {23},
 id = {c149a202-0c76-316c-9450-9b0e81ae516f},
 created = {2013-06-06T21:07:22.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of Aβ42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of Aβ fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of Aβ(16-22), an amyloid-forming peptide fragment of full-length Aβ, successively with and without scyllo-inositol and its inactive stereoisomer chiro-inositol. Both stereoisomers bind monomers and disordered aggregates with similar affinities of 10-120 mM, whereas binding to β-sheet-containing protofibrils yields affinities of 0.2-0.5 mM commensurate with in vitro inhibitory concentrations of scyllo-inositol. Moreover, scyllo-inositol displays a higher binding specificity for phenylalanine-lined grooves on the protofibril surface, suggesting that scyllo-inositol coats the surface of Aβ protofibrils and disrupts their lateral stacking into amyloid fibrils.},
 bibtype = {article},
 author = {Li, Grace and Pomès, Régis},
 doi = {10.1021/jp311350r},
 journal = {The Journal of Physical Chemistry B},
 number = {22}
}

Alzheimer's disease (AD) is a severe neurodegenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of Aβ42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of Aβ fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of Aβ(16-22), an amyloid-forming peptide fragment of full-length Aβ, successively with and without scyllo-inositol and its inactive stereoisomer chiro-inositol. Both stereoisomers bind monomers and disordered aggregates with similar affinities of 10-120 mM, whereas binding to β-sheet-containing protofibrils yields affinities of 0.2-0.5 mM commensurate with in vitro inhibitory concentrations of scyllo-inositol. Moreover, scyllo-inositol displays a higher binding specificity for phenylalanine-lined grooves on the protofibril surface, suggesting that scyllo-inositol coats the surface of Aβ protofibrils and disrupts their lateral stacking into amyloid fibrils.

@article{
 title = {Catalysis of Na+ permeation in the bacterial sodium channel NavAb.},
 type = {article},
 year = {2013},
 volume = {110},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23803856},
 month = {6},
 day = {26},
 id = {5adb4ea7-acf3-36f6-9b8d-e7856462ab64},
 created = {2013-07-09T19:03:35.000Z},
 accessed = {2013-07-01},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Determination of a high-resolution 3D structure of voltage-gated sodium channel NaVAb opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na(+) through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of NaVAb in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 μs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na(+) through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na(+) between the extracellular medium and the central cavity of the channel. Analysis of Na(+) dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na(+) ions, with a computed rate of translocation of (6 ± 1) × 10(6) ions⋅s(-1) that is consistent with expectations from electrophysiological studies. The binding of Na(+) is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na(+) ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquid-like energy landscape propitious to Na(+) diffusion. By stabilizing multiple ionic occupancy states while helping Na(+) ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na(+) permeation.},
 bibtype = {article},
 author = {Chakrabarti, Nilmadhab and Ing, Christopher and Payandeh, Jian and Zheng, Ning and Catterall, William a and Pomès, Régis},
 doi = {10.1073/pnas.1309452110},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {28}
}

Determination of a high-resolution 3D structure of voltage-gated sodium channel NaVAb opens the way to elucidating the mechanism of ion conductance and selectivity. To examine permeation of Na(+) through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of NaVAb in an explicit, hydrated lipid bilayer at 0 mV in 150 mM NaCl, for a total simulation time of 21.6 μs. Although the cytoplasmic end of the pore is closed, reversible influx and efflux of Na(+) through the selectivity filter occurred spontaneously during simulations, leading to equilibrium movement of Na(+) between the extracellular medium and the central cavity of the channel. Analysis of Na(+) dynamics reveals a knock-on mechanism of ion permeation characterized by alternating occupancy of the channel by 2 and 3 Na(+) ions, with a computed rate of translocation of (6 ± 1) × 10(6) ions⋅s(-1) that is consistent with expectations from electrophysiological studies. The binding of Na(+) is intimately coupled to conformational isomerization of the four E177 side chains lining the extracellular end of the selectivity filter. The reciprocal coordination of variable numbers of Na(+) ions and carboxylate groups leads to their condensation into ionic clusters of variable charge and spatial arrangement. Structural fluctuations of these ionic clusters result in a myriad of ion binding modes and foster a highly degenerate, liquid-like energy landscape propitious to Na(+) diffusion. By stabilizing multiple ionic occupancy states while helping Na(+) ions diffuse within the selectivity filter, the conformational flexibility of E177 side chains underpins the knock-on mechanism of Na(+) permeation.

@article{
 title = {Peregrination of the selectivity filter delineates the pore of the human voltage-gated proton channel hHV1},
 type = {article},
 year = {2013},
 websites = {http://www.jgp.org/cgi/doi/10.1085/jgp.201311045},
 month = {11},
 day = {11},
 id = {5f6ffcab-4d57-3634-bc9a-7c9eda428ad3},
 created = {2013-11-14T14:11:10.000Z},
 accessed = {2013-11-12},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Morgan, D. and Musset, B. and Kulleperuma, K. and Smith, S. M. E. and Rajan, S. and Cherny, V. V. and Pomes, R. and DeCoursey, T. E.},
 doi = {10.1085/jgp.201311045},
 journal = {The Journal of General Physiology}
}

@article{
 title = {Accelerating convergence in molecular dynamics simulations of solutes in lipid membranes by conducting a random walk along the bilayer normal},
 type = {article},
 year = {2013},
 volume = {9},
 id = {12a4bbc0-1c5d-3363-85e1-2fca26a8555d},
 created = {2018-06-08T17:39:27.908Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.908Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {All molecular dynamics simulations are susceptible to sampling errors, which degrade the accuracy and precision of observed values. The statistical convergence of simulations containing atomistic lipid bilayers is limited by the slow relaxation of the lipid phase, which can exceed hundreds of nanoseconds. These long conformational autocorrelation times are exacerbated in the presence of charged solutes, which can induce significant distortions of the bilayer structure. Such long relaxation times represent hidden barriers that induce systematic sampling errors in simulations of solute insertion. To identify optimal methods for enhancing sampling efficiency, we quantitatively evaluate convergence rates using generalized ensemble sampling algorithms in calculations of the potential of mean force for the insertion of the ionic side chain analog of arginine in a lipid bilayer. Umbrella sampling (US) is used to restrain solute insertion depth along the bilayer normal, the order parameter commonly used in simulations of molecular solutes in lipid bilayers. When US simulations are modified to conduct random walks along the bilayer normal using a Hamiltonian exchange algorithm, systematic sampling errors are eliminated more rapidly and the rate of statistical convergence of the standard free energy of binding of the solute to the lipid bilayer is increased 3-fold. We compute the ratio of the replica flux transmitted across a defined region of the order parameter to the replica flux that entered that region in Hamiltonian exchange simulations. We show that this quantity, the transmission factor, identifies sampling barriers in degrees of freedom orthogonal to the order parameter. The transmission factor is used to estimate the depth-dependent conformational  autocorrelation times of the simulation system, some of which exceed the simulation time, and thereby identify solute insertion depths that are prone to systematic sampling errors and estimate the lower bound of the amount of sampling that is required to resolve these sampling errors. Finally, we extend our simulations and verify that the conformational autocorrelation times estimated by the transmission factor accurately predict correlation times that exceed the simulation time scale - something that, to our knowledge, has never before been achieved. © 2013 American Chemical Society.},
 bibtype = {article},
 author = {Neale, C. and Madill, C. and Rauscher, S. and Pomès, R.},
 doi = {10.1021/ct301005b},
 journal = {Journal of Chemical Theory and Computation},
 number = {8}
}

All molecular dynamics simulations are susceptible to sampling errors, which degrade the accuracy and precision of observed values. The statistical convergence of simulations containing atomistic lipid bilayers is limited by the slow relaxation of the lipid phase, which can exceed hundreds of nanoseconds. These long conformational autocorrelation times are exacerbated in the presence of charged solutes, which can induce significant distortions of the bilayer structure. Such long relaxation times represent hidden barriers that induce systematic sampling errors in simulations of solute insertion. To identify optimal methods for enhancing sampling efficiency, we quantitatively evaluate convergence rates using generalized ensemble sampling algorithms in calculations of the potential of mean force for the insertion of the ionic side chain analog of arginine in a lipid bilayer. Umbrella sampling (US) is used to restrain solute insertion depth along the bilayer normal, the order parameter commonly used in simulations of molecular solutes in lipid bilayers. When US simulations are modified to conduct random walks along the bilayer normal using a Hamiltonian exchange algorithm, systematic sampling errors are eliminated more rapidly and the rate of statistical convergence of the standard free energy of binding of the solute to the lipid bilayer is increased 3-fold. We compute the ratio of the replica flux transmitted across a defined region of the order parameter to the replica flux that entered that region in Hamiltonian exchange simulations. We show that this quantity, the transmission factor, identifies sampling barriers in degrees of freedom orthogonal to the order parameter. The transmission factor is used to estimate the depth-dependent conformational autocorrelation times of the simulation system, some of which exceed the simulation time, and thereby identify solute insertion depths that are prone to systematic sampling errors and estimate the lower bound of the amount of sampling that is required to resolve these sampling errors. Finally, we extend our simulations and verify that the conformational autocorrelation times estimated by the transmission factor accurately predict correlation times that exceed the simulation time scale - something that, to our knowledge, has never before been achieved. © 2013 American Chemical Society.

@article{
 title = {Structure of saposin A lipoprotein discs.},
 type = {article},
 year = {2012},
 pages = {2908-2912},
 volume = {109},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/22308394},
 month = {2},
 day = {2},
 id = {4bf5937e-f09d-3653-89b4-dbc4bed3be0d},
 created = {2012-02-21T21:42:47.000Z},
 accessed = {2012-02-21},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The saposins are small, membrane-active proteins that exist in both soluble and lipid-bound states. Saposin A has roles in sphingolipid catabolism and transport and is required for the breakdown of galactosylceramide by β-galactosylceramidase. In the absence of lipid, saposin A adopts a closed monomeric apo conformation typical of this family. To study a lipid-bound state of this protein, we determined the crystal structure of saposin A in the presence of detergent to 1.9 Å resolution. The structure reveals two chains of saposin A in an open conformation encapsulating 40 internally bound detergent molecules organized in a highly ordered bilayer-like hydrophobic core. The complex provides a high-resolution view of a discoidal lipoprotein particle in which all of the internalized acyl chains are resolved. Saposin A lipoprotein discs exhibit limited selectivity with respect to the incorporated lipid, and can solubilize phospholipids, sphingolipids, and cholesterol into discrete, monodisperse particles with mass of approximately 27 kDa. These discs may be the smallest possible lipoprotein structures that are stabilized by lipid self-assembly.},
 bibtype = {article},
 author = {Popovic, Konstantin and Holyoake, John and Pomès, Régis and Privé, Gilbert G},
 doi = {10.1073/pnas.1115743109},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {8}
}

The saposins are small, membrane-active proteins that exist in both soluble and lipid-bound states. Saposin A has roles in sphingolipid catabolism and transport and is required for the breakdown of galactosylceramide by β-galactosylceramidase. In the absence of lipid, saposin A adopts a closed monomeric apo conformation typical of this family. To study a lipid-bound state of this protein, we determined the crystal structure of saposin A in the presence of detergent to 1.9 Å resolution. The structure reveals two chains of saposin A in an open conformation encapsulating 40 internally bound detergent molecules organized in a highly ordered bilayer-like hydrophobic core. The complex provides a high-resolution view of a discoidal lipoprotein particle in which all of the internalized acyl chains are resolved. Saposin A lipoprotein discs exhibit limited selectivity with respect to the incorporated lipid, and can solubilize phospholipids, sphingolipids, and cholesterol into discrete, monodisperse particles with mass of approximately 27 kDa. These discs may be the smallest possible lipoprotein structures that are stabilized by lipid self-assembly.

@article{
 title = {Binding of inositol stereoisomers to model amyloidogenic peptides.},
 type = {article},
 year = {2012},
 pages = {1111-9},
 volume = {116},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/22091989},
 month = {1},
 day = {26},
 id = {1150b74e-d453-36ef-b1ca-4c7f3fbc5f26},
 created = {2012-02-21T21:45:43.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The self-aggregation of proteins into amyloid fibrils is a pathological hallmark of numerous incurable diseases such as Alzheimer's disease. scyllo-Inositol is a stereochemistry-dependent in vitro inhibitor of amyloid formation. As the first step to elucidate its mechanism of action, we present molecular dynamics simulations of scyllo-inositol and its inactive stereoisomer, chiro-inositol, with simple peptide models, alanine dipeptide (ADP) and (Gly-Ala)(4). We characterize molecular interactions and compute equilibrium binding constants between inositol and ADP as well as, successively, monomers, amorphous aggregates, and fibril-like β-sheet aggregates of (Gly-Ala)(4). Inositol interacts weakly with all peptide systems considered, with millimolar to molar affinities, and displaces the conformational equilibria of ADP but not of the (Gly-Ala)(4) systems. However, scyllo- and chiro-inositol adopt different binding modes on the surface of β-sheet aggregates. These results suggest that inositol does not inhibit amyloid formation by breaking up preformed aggregates but rather by binding to the surface of prefibrillar aggregates.},
 bibtype = {article},
 author = {Li, Grace and Rauscher, Sarah and Baud, Stéphanie and Pomès, Régis},
 doi = {10.1021/jp208567n},
 journal = {The Journal of Physical Chemistry B},
 number = {3}
}

The self-aggregation of proteins into amyloid fibrils is a pathological hallmark of numerous incurable diseases such as Alzheimer's disease. scyllo-Inositol is a stereochemistry-dependent in vitro inhibitor of amyloid formation. As the first step to elucidate its mechanism of action, we present molecular dynamics simulations of scyllo-inositol and its inactive stereoisomer, chiro-inositol, with simple peptide models, alanine dipeptide (ADP) and (Gly-Ala)(4). We characterize molecular interactions and compute equilibrium binding constants between inositol and ADP as well as, successively, monomers, amorphous aggregates, and fibril-like β-sheet aggregates of (Gly-Ala)(4). Inositol interacts weakly with all peptide systems considered, with millimolar to molar affinities, and displaces the conformational equilibria of ADP but not of the (Gly-Ala)(4) systems. However, scyllo- and chiro-inositol adopt different binding modes on the surface of β-sheet aggregates. These results suggest that inositol does not inhibit amyloid formation by breaking up preformed aggregates but rather by binding to the surface of prefibrillar aggregates.

@article{
 title = {Improving Internal Peptide Dynamics in the Coarse-Grained MARTINI Model : Toward Large-Scale Simulations of Amyloid- and Elastin-like Peptides},
 type = {article},
 year = {2012},
 pages = {1774-1785},
 volume = {8},
 id = {9a8bfed9-9841-3007-80b2-e8113148309d},
 created = {2012-04-09T20:15:58.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {We present an extension of the coarse-grained MARTINI model for proteins and apply this extension to amyloidand elastin-like peptides. Atomistic simulations of tetrapeptides, octapeptides, and longer peptides in solution are used as a reference to parametrize a set of pseudodihedral potentials that describe the internal flexibility of MARTINI peptides. We assess the performance of the resulting model in reproducing various structural properties computed from atomistic trajectories of peptides in water. The addition of new dihedral angle potentials improves agreement with the contact maps computed from atomistic simulations significantly. We also address the question of which parameters derived from atomistic trajectories are transferable between different lengths of peptides. The modified coarse-grained model shows reasonable transferability of parameters for the amyloid- and elastin-like peptides. In addition, the improved coarse-grained model is also applied to investigate the self-assembly of β-sheet forming peptides on the microsecond time scale. The octapeptides SNNFGAIL and (GV)4 are used to examine peptide aggregation in different environments, in water, and at the water−octane interface. At the interface, peptide adsorption occurs rapidly, and peptides spontaneously aggregate in favor of stretched conformers resembling β-strands.},
 bibtype = {article},
 author = {Seo, Mikyung and Rauscher, Sarah and Tieleman, D Peter},
 journal = {Journal of Chemical Theory and Computation},
 number = {5}
}

We present an extension of the coarse-grained MARTINI model for proteins and apply this extension to amyloidand elastin-like peptides. Atomistic simulations of tetrapeptides, octapeptides, and longer peptides in solution are used as a reference to parametrize a set of pseudodihedral potentials that describe the internal flexibility of MARTINI peptides. We assess the performance of the resulting model in reproducing various structural properties computed from atomistic trajectories of peptides in water. The addition of new dihedral angle potentials improves agreement with the contact maps computed from atomistic simulations significantly. We also address the question of which parameters derived from atomistic trajectories are transferable between different lengths of peptides. The modified coarse-grained model shows reasonable transferability of parameters for the amyloid- and elastin-like peptides. In addition, the improved coarse-grained model is also applied to investigate the self-assembly of β-sheet forming peptides on the microsecond time scale. The octapeptides SNNFGAIL and (GV)4 are used to examine peptide aggregation in different environments, in water, and at the water−octane interface. At the interface, peptide adsorption occurs rapidly, and peptides spontaneously aggregate in favor of stretched conformers resembling β-strands.

@article{
 title = {Structural asymmetry in the magnesium channel CorA points to sequential allosteric regulation.},
 type = {article},
 year = {2012},
 pages = {5-10},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23112165},
 month = {10},
 day = {29},
 id = {757bcbeb-c6ea-30f6-9312-20e767a16229},
 created = {2012-11-14T21:57:43.000Z},
 accessed = {2012-11-14},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Magnesium ions (Mg(2+)) are essential for life, but the mechanisms regulating their transport into and out of cells remain poorly understood. The CorA-Mrs2-Alr1 superfamily of Mg(2+) channels represents the most prevalent group of proteins enabling Mg(2+) ions to cross membranes. Thermotoga maritima CorA (TmCorA) is the only member of this protein family whose complete 3D fold is known. Here, we report the crystal structure of a mutant in the presence and absence of divalent ions and compare it with previous divalent ion-bound TmCorA structures. With Mg(2+) present, this structure shows binding of a hydrated Mg(2+) ion to the periplasmic Gly-Met-Asn (GMN) motif, revealing clues of ion selectivity in this unique channel family. In the absence of Mg(2+), TmCorA displays an unexpected asymmetric conformation caused by radial and lateral tilts of protomers that leads to bending of the central, pore-lining helix. Molecular dynamics simulations support these movements, including a bell-like deflection. Mass spectrometric analysis confirms that major proteolytic cleavage occurs within a region that is selectively exposed by such a bell-like bending motion. Our results point to a sequential allosteric model of regulation, where intracellular Mg(2+) binding locks TmCorA in a symmetric, transport-incompetent conformation and loss of intracellular Mg(2+) causes an asymmetric, potentially influx-competent conformation of the channel.},
 bibtype = {article},
 author = {Pfoh, Roland and Li, Angela and Chakrabarti, Nilmadhab and Payandeh, Jian and Pomès, Régis and Pai, Emil F},
 doi = {10.1073/pnas.1209018109},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {25}
}

Magnesium ions (Mg(2+)) are essential for life, but the mechanisms regulating their transport into and out of cells remain poorly understood. The CorA-Mrs2-Alr1 superfamily of Mg(2+) channels represents the most prevalent group of proteins enabling Mg(2+) ions to cross membranes. Thermotoga maritima CorA (TmCorA) is the only member of this protein family whose complete 3D fold is known. Here, we report the crystal structure of a mutant in the presence and absence of divalent ions and compare it with previous divalent ion-bound TmCorA structures. With Mg(2+) present, this structure shows binding of a hydrated Mg(2+) ion to the periplasmic Gly-Met-Asn (GMN) motif, revealing clues of ion selectivity in this unique channel family. In the absence of Mg(2+), TmCorA displays an unexpected asymmetric conformation caused by radial and lateral tilts of protomers that leads to bending of the central, pore-lining helix. Molecular dynamics simulations support these movements, including a bell-like deflection. Mass spectrometric analysis confirms that major proteolytic cleavage occurs within a region that is selectively exposed by such a bell-like bending motion. Our results point to a sequential allosteric model of regulation, where intracellular Mg(2+) binding locks TmCorA in a symmetric, transport-incompetent conformation and loss of intracellular Mg(2+) causes an asymmetric, potentially influx-competent conformation of the channel.

@book{
 title = {Structural disorder and protein elasticity},
 type = {book},
 year = {2012},
 source = {Advances in Experimental Medicine and Biology},
 volume = {725},
 id = {2c32fe4c-bc1e-31f6-858f-e47c8305555b},
 created = {2018-06-08T17:39:27.560Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.560Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {An emerging class of disordered proteins underlies the elasticity of many biological tissues. Elastomeric proteins are essential to the function of biological machinery as diverse as the human arterial wall, the capture spiral of spider webs and the jumping mechanism of fleas. In this chapter, we review what is known about the molecular basis and the functional role of structural disorder in protein elasticity. In general, the elastic recoil of proteins is due to a combination of internal energy and entropy. In rubber-like elastomeric proteins, the dominant driving force is the increased entropy of the relaxed state relative to the stretched state. Aggregates of these proteins are intrinsically disordered or fuzzy, with high polypeptide chain entropy. We focus our discussion on the sequence, structure and function of five rubber-like elastomeric proteins, elastin, resilin, spider silk, abductin and ColP. Although we group these disordered elastomers together into one class of proteins, they exhibit a broad range of sequence motifs, mechanical properties and biological functions. Understanding how sequence modulates both disorder and elasticity will help advance the rational design of elastic biomaterials such as artificial skin and vascular grafts. © 2012 Landes Bioscience and Springer Science+Business Media.},
 bibtype = {book},
 author = {Rauscher, S. and Pomès, R.},
 doi = {10.1007/978-1-4614-0659-4_10}
}

An emerging class of disordered proteins underlies the elasticity of many biological tissues. Elastomeric proteins are essential to the function of biological machinery as diverse as the human arterial wall, the capture spiral of spider webs and the jumping mechanism of fleas. In this chapter, we review what is known about the molecular basis and the functional role of structural disorder in protein elasticity. In general, the elastic recoil of proteins is due to a combination of internal energy and entropy. In rubber-like elastomeric proteins, the dominant driving force is the increased entropy of the relaxed state relative to the stretched state. Aggregates of these proteins are intrinsically disordered or fuzzy, with high polypeptide chain entropy. We focus our discussion on the sequence, structure and function of five rubber-like elastomeric proteins, elastin, resilin, spider silk, abductin and ColP. Although we group these disordered elastomers together into one class of proteins, they exhibit a broad range of sequence motifs, mechanical properties and biological functions. Understanding how sequence modulates both disorder and elasticity will help advance the rational design of elastic biomaterials such as artificial skin and vascular grafts. © 2012 Landes Bioscience and Springer Science+Business Media.

@article{
 title = {Size dependence of cavity volume: A molecular dynamics study},
 type = {article},
 year = {2012},
 keywords = {Hydration,Molecular dynamics,Solute size,Thermodynamics,Volume},
 volume = {161},
 id = {4ca04b97-ef45-38a7-9574-fa5d6d265e83},
 created = {2018-06-08T17:39:27.797Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.797Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Partial molar volume, V°, has been used as a tool to sample solute hydration for decades. The efficacy of volumetric investigations of hydration depends on our ability to reliably discriminate between the cavity, V C , and interaction, V I , contributions to the partial molar volume. The cavity volume, V C , consists of the intrinsic volume, V M , of a solute molecule and the thermal volume, V T , with the latter representing the volume of the effective void created around the solute. In this work, we use molecular dynamics simulations in conjunction with the Kirkwood-Buff theory to compute the partial molar volumes for organic solutes of varying sizes in water. We perform our computations using the Lennard-Jones and Coulombic pair potentials as well as truncated potentials which contain only the Lennard-Jones but not the Coulombic contribution. The partial molar volume computed with the Lennard-Jones potentials in the absence of the Coulombic term nearly coincides with the cavity volume, V C . We determine the thermal volume, V T , for each compound by subtracting its van der Waals volume, V W , from V C . Finally, we apply the spherical approximation of solute geometry to evaluate the thickness of the thermal volume, δ. Our results reveal an increase in the thickness of thermal volume, δ, with an increase in the size of the solute. This finding may be related to dewetting of large nonpolar solutes and the concomitant increase in the compressibility of water of hydration. © 2011 Elsevier B.V. All rights reserved.},
 bibtype = {article},
 author = {Patel, N. and Dubins, D.N. and Pomès, R. and Chalikian, T.V.},
 doi = {10.1016/j.bpc.2011.10.001},
 journal = {Biophysical Chemistry}
}

Partial molar volume, V°, has been used as a tool to sample solute hydration for decades. The efficacy of volumetric investigations of hydration depends on our ability to reliably discriminate between the cavity, V C , and interaction, V I , contributions to the partial molar volume. The cavity volume, V C , consists of the intrinsic volume, V M , of a solute molecule and the thermal volume, V T , with the latter representing the volume of the effective void created around the solute. In this work, we use molecular dynamics simulations in conjunction with the Kirkwood-Buff theory to compute the partial molar volumes for organic solutes of varying sizes in water. We perform our computations using the Lennard-Jones and Coulombic pair potentials as well as truncated potentials which contain only the Lennard-Jones but not the Coulombic contribution. The partial molar volume computed with the Lennard-Jones potentials in the absence of the Coulombic term nearly coincides with the cavity volume, V C . We determine the thermal volume, V T , for each compound by subtracting its van der Waals volume, V W , from V C . Finally, we apply the spherical approximation of solute geometry to evaluate the thickness of the thermal volume, δ. Our results reveal an increase in the thickness of thermal volume, δ, with an increase in the size of the solute. This finding may be related to dewetting of large nonpolar solutes and the concomitant increase in the compressibility of water of hydration. © 2011 Elsevier B.V. All rights reserved.

@article{
 title = {Improving internal peptide dynamics in the coarse-grained MARTINI model: Toward large-scale simulations of amyloid- and elastin-like peptides},
 type = {article},
 year = {2012},
 volume = {8},
 id = {5619baf8-2571-3173-a254-a8aec45a911e},
 created = {2018-06-08T17:39:28.030Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.030Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {We present an extension of the coarse-grained MARTINI model for proteins and apply this extension to amyloid- and elastin-like peptides. Atomistic simulations of tetrapeptides, octapeptides, and longer peptides in solution are used as a reference to parametrize a set of pseudodihedral potentials that describe the internal flexibility of MARTINI peptides. We assess the performance of the resulting model in reproducing various structural properties computed from atomistic trajectories of peptides in water. The addition of new dihedral angle potentials improves agreement with the contact maps computed from atomistic simulations significantly. We also address the question of which parameters derived from atomistic trajectories are transferable between different lengths of peptides. The modified coarse-grained model shows reasonable transferability of parameters for the amyloid- and elastin-like peptides. In addition, the improved coarse-grained model is also applied to investigate the self-assembly of β-sheet forming peptides on the microsecond time scale. The octapeptides SNNFGAIL and (GV)  4  are used to examine peptide aggregation in different environments, in water, and at the water-octane interface. At the interface, peptide adsorption occurs rapidly, and peptides spontaneously aggregate in favor of stretched conformers resembling β-strands. © 2012 American Chemical Society.},
 bibtype = {article},
 author = {Seo, M. and Rauscher, S. and Pomès, R. and Tieleman, D.P.},
 doi = {10.1021/ct200876v},
 journal = {Journal of Chemical Theory and Computation},
 number = {5}
}

We present an extension of the coarse-grained MARTINI model for proteins and apply this extension to amyloid- and elastin-like peptides. Atomistic simulations of tetrapeptides, octapeptides, and longer peptides in solution are used as a reference to parametrize a set of pseudodihedral potentials that describe the internal flexibility of MARTINI peptides. We assess the performance of the resulting model in reproducing various structural properties computed from atomistic trajectories of peptides in water. The addition of new dihedral angle potentials improves agreement with the contact maps computed from atomistic simulations significantly. We also address the question of which parameters derived from atomistic trajectories are transferable between different lengths of peptides. The modified coarse-grained model shows reasonable transferability of parameters for the amyloid- and elastin-like peptides. In addition, the improved coarse-grained model is also applied to investigate the self-assembly of β-sheet forming peptides on the microsecond time scale. The octapeptides SNNFGAIL and (GV) 4 are used to examine peptide aggregation in different environments, in water, and at the water-octane interface. At the interface, peptide adsorption occurs rapidly, and peptides spontaneously aggregate in favor of stretched conformers resembling β-strands. © 2012 American Chemical Society.

@article{
 title = {Parsing partial molar volumes of small molecules: a molecular dynamics study.},
 type = {article},
 year = {2011},
 pages = {4856-4862},
 volume = {115},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/21466176},
 institution = {Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.},
 id = {736ebca3-aada-3966-817c-dcb8b2fc5dea},
 created = {2011-12-05T17:36:31.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {We used molecular dynamics (MD) simulations in conjunction with the Kirkwood-Buff theory to compute the partial molar volumes for a number of small solutes of various chemical natures. We repeated our computations using modified pair potentials, first, in the absence of the Coulombic term and, second, in the absence of the Coulombic and the attractive Lennard-Jones terms. Comparison of our results with experimental data and the volumetric results of Monte Carlo simulation with hard sphere potentials and scaled particle theory-based computations led us to conclude that, for small solutes, the partial molar volume computed with the Lennard-Jones potential in the absence of the Coulombic term nearly coincides with the cavity volume. On the other hand, MD simulations carried out with the pair interaction potentials containing only the repulsive Lennard-Jones term produce unrealistically large partial molar volumes of solutes that are close to their excluded volumes. Our simulation results are in good agreement with the reported schemes for parsing partial molar volume data on small solutes. In particular, our determined interaction volumes() and the thickness of the thermal volume for individual compounds are in good agreement with empirical estimates. This work is the first computational study that supports and lends credence to the practical algorithms of parsing partial molar volume data that are currently in use for molecular interpretations of volumetric data.},
 bibtype = {article},
 author = {Patel, Nisha and Dubins, David N and Pomès, Régis and Chalikian, Tigran V},
 journal = {The Journal of Physical Chemistry B},
 number = {16}
}

We used molecular dynamics (MD) simulations in conjunction with the Kirkwood-Buff theory to compute the partial molar volumes for a number of small solutes of various chemical natures. We repeated our computations using modified pair potentials, first, in the absence of the Coulombic term and, second, in the absence of the Coulombic and the attractive Lennard-Jones terms. Comparison of our results with experimental data and the volumetric results of Monte Carlo simulation with hard sphere potentials and scaled particle theory-based computations led us to conclude that, for small solutes, the partial molar volume computed with the Lennard-Jones potential in the absence of the Coulombic term nearly coincides with the cavity volume. On the other hand, MD simulations carried out with the pair interaction potentials containing only the repulsive Lennard-Jones term produce unrealistically large partial molar volumes of solutes that are close to their excluded volumes. Our simulation results are in good agreement with the reported schemes for parsing partial molar volume data on small solutes. In particular, our determined interaction volumes() and the thickness of the thermal volume for individual compounds are in good agreement with empirical estimates. This work is the first computational study that supports and lends credence to the practical algorithms of parsing partial molar volume data that are currently in use for molecular interpretations of volumetric data.

@article{
 title = {On the molecular basis of uracil recognition in DNA: comparative study of T-A versus U-A structure, dynamics and open base pair kinetics},
 type = {article},
 year = {2011},
 pages = {767-780},
 volume = {39},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/20876689},
 publisher = {Oxford University Press},
 institution = {School of Chemistry, National University of Ireland, Galway (NUIG), Galway, Ireland. elisa.fadda@nuigalway.ie},
 id = {b3dfd861-4ef3-3d14-8654-912eb9f71417},
 created = {2011-12-07T04:42:28.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Uracil (U) can be found in DNA as a mismatch paired either to adenine (A) or to guanine (G). Removal of U from DNA is performed by a class of enzymes known as uracilDNAglycosylases (UDG). Recent studies suggest that recognition of UA and UG mismatches by UDG takes place via an extra-helical mechanism. In this work, we use molecular dynamics simulations to analyze the structure, dynamics and open base pair kinetics of UA base pairs relative to their natural TA counterpart in 12 dodecamers. Our results show that the presence of U does not alter the local conformation of B-DNA. Breathing dynamics and base pair closing kinetics are only weakly dependent on the presence of U versus T, with open TA and UA pairs lifetimes in the nanosecond timescale. Additionally, we observed spontaneous base flipping in UA pairs. We analyze the structure and dynamics for this event and compare the results to available crystallographic data of open base pair conformations. Our results are in agreement with both structural and kinetic data derived from NMR imino proton exchange measurements, providing the first detailed description at the molecular level of elusive events such as spontaneous base pair opening and flipping in mismatched UA sequences in DNA. Based on these results, we propose that base pair flipping can occur spontaneously at room temperature via a 3-step mechanism with an open base pair intermediate. Implications for the molecular basis of U recognition by UDG are discussed.},
 bibtype = {article},
 author = {Fadda, Elisa and Pomès, Régis},
 journal = {Nucleic Acids Research},
 number = {2}
}

Uracil (U) can be found in DNA as a mismatch paired either to adenine (A) or to guanine (G). Removal of U from DNA is performed by a class of enzymes known as uracilDNAglycosylases (UDG). Recent studies suggest that recognition of UA and UG mismatches by UDG takes place via an extra-helical mechanism. In this work, we use molecular dynamics simulations to analyze the structure, dynamics and open base pair kinetics of UA base pairs relative to their natural TA counterpart in 12 dodecamers. Our results show that the presence of U does not alter the local conformation of B-DNA. Breathing dynamics and base pair closing kinetics are only weakly dependent on the presence of U versus T, with open TA and UA pairs lifetimes in the nanosecond timescale. Additionally, we observed spontaneous base flipping in UA pairs. We analyze the structure and dynamics for this event and compare the results to available crystallographic data of open base pair conformations. Our results are in agreement with both structural and kinetic data derived from NMR imino proton exchange measurements, providing the first detailed description at the molecular level of elusive events such as spontaneous base pair opening and flipping in mismatched UA sequences in DNA. Based on these results, we propose that base pair flipping can occur spontaneously at room temperature via a 3-step mechanism with an open base pair intermediate. Implications for the molecular basis of U recognition by UDG are discussed.

@article{
 title = {Molecular mechanism of β-sheet self-organization at water-hydrophobic interfaces.},
 type = {article},
 year = {2011},
 pages = {1-22},
 volume = {79},
 websites = {http://doi.wiley.com/10.1002/prot.22854},
 institution = {Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada.},
 id = {7b36d456-22f7-3df0-840a-9d540224b024},
 created = {2011-12-07T04:42:31.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The capacity to form -sheet structure and to self-organize into amyloid aggregates is a property shared by many proteins. Severe neurodegenerative pathologies such as Alzheimer's disease are thought to involve the interaction of amyloidogenic protein oligomers with neuronal membranes. To understand the experimentally observed catalysis of amyloid formation by lipid membranes and other water-hydrophobic interfaces, we examine the physico-chemical basis of peptide adsorption and aggregation in a model membrane using atomistic molecular simulations. Blocked octapeptides with simple, repetitive sequences, (Gly-Ala), and (Gly-Val), are used as models of -sheet-forming polypeptide chains found in the core of amyloid fibrils. In the presence of an n-octane phase mimicking the core of lipid membranes, the peptides spontaneously partition at the octane-water interface. The adsorption of nonpolar sidechains displaces the peptides' conformational equilibrium from a heterogeneous ensemble characterized by a high degree of structural disorder toward a more ordered ensemble favoring -hairpins and elongated -strands. At the interface, peptides spontaneously aggregate and rapidly evolve -sheet structure on a 10 to 100 ns time scale, while aqueous aggregates remain amorphous. Catalysis of -sheet formation results from the combination of the hydrophobic effect and of reduced conformational entropy of the polypeptide chain. While the former drives interfacial partition and displaces the conformational equilibrium of monomeric peptides, the planar interface further facilitates -sheet organization by increasing peptide concentration and reducing the dimensionality of self-assembly from three to two. These findings suggest a general mechanism for the formation of -sheets on the surface of globular proteins and for amyloid self-organization at hydrophobic interfaces.},
 bibtype = {article},
 author = {Nikolic, Ana and Baud, Stéphanie and Rauscher, Sarah and Pomès, Régis},
 journal = {Proteins},
 number = {1}
}

The capacity to form -sheet structure and to self-organize into amyloid aggregates is a property shared by many proteins. Severe neurodegenerative pathologies such as Alzheimer's disease are thought to involve the interaction of amyloidogenic protein oligomers with neuronal membranes. To understand the experimentally observed catalysis of amyloid formation by lipid membranes and other water-hydrophobic interfaces, we examine the physico-chemical basis of peptide adsorption and aggregation in a model membrane using atomistic molecular simulations. Blocked octapeptides with simple, repetitive sequences, (Gly-Ala), and (Gly-Val), are used as models of -sheet-forming polypeptide chains found in the core of amyloid fibrils. In the presence of an n-octane phase mimicking the core of lipid membranes, the peptides spontaneously partition at the octane-water interface. The adsorption of nonpolar sidechains displaces the peptides' conformational equilibrium from a heterogeneous ensemble characterized by a high degree of structural disorder toward a more ordered ensemble favoring -hairpins and elongated -strands. At the interface, peptides spontaneously aggregate and rapidly evolve -sheet structure on a 10 to 100 ns time scale, while aqueous aggregates remain amorphous. Catalysis of -sheet formation results from the combination of the hydrophobic effect and of reduced conformational entropy of the polypeptide chain. While the former drives interfacial partition and displaces the conformational equilibrium of monomeric peptides, the planar interface further facilitates -sheet organization by increasing peptide concentration and reducing the dimensionality of self-assembly from three to two. These findings suggest a general mechanism for the formation of -sheets on the surface of globular proteins and for amyloid self-organization at hydrophobic interfaces.

@article{
 title = {Statistical Convergence of Equilibrium Properties in Simulations of Molecular Solutes Embedded in Lipid Bilayers},
 type = {article},
 year = {2011},
 pages = {111005164626009},
 websites = {http://pubs.acs.org/doi/abs/10.1021/ct200316w},
 id = {8572f454-d5d2-3ba1-8025-dd9a641e4c29},
 created = {2011-12-07T04:42:34.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Neale, Chris and Bennett, W F Drew and Tieleman, D Peter and Pomès, Régis},
 journal = {Journal of Chemical Theory and Computation}
}

@article{
 title = {Computational approaches to the rational design of nanoemulsions , polymeric micelles , and dendrimers for drug delivery},
 type = {article},
 year = {2011},
 keywords = {40,considered new,drug candidates hydrophobic,drug formulations,drug material compatibility,estimated,molecular simulation,nanoparticle,nanoparticles drug delivery,small molecules,theoretical prediction},
 pages = {1-17},
 websites = {http://dx.doi.org/10.1016/j.nano.2011.05.006},
 publisher = {Elsevier Inc.},
 id = {e32934db-5255-3fce-81e6-f8e5b8509880},
 created = {2011-12-07T04:42:43.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Nanoparticles are promising drug delivery systems whose selection and optimization can be gainfully conducted by theoretical methods. This review is targeted to experimentalists who are interested in enhancing their time and cost efficiency through the incorporation of theoretical approaches. This review thus begins with a brief overview of theoretical approaches available to the development of contem- porary drug delivery systems. Approaches include solubility parameters, Flory-Huggins theory, analytical predictions of partition coeffi- cients, and molecular simulations. These methods are then compared as they relate to the optimization of drug-material pairs using important performance-related parameters including the size of the delivery particles, their surface properties, and the compatibility of the materials with the drug to be sequestered. Next, this review explores contemporary efforts to optimize a selection of existing nanoparticle platforms, including nanoemulsions, linear and star-shaped block co-polymer micelles, and dendrimers. The review concludes with an outlook on the challenges remaining in the successful application of these theoretical methods to the development of new drug formulations.},
 bibtype = {article},
 author = {Huynh, Loan and Neale, Chris and Pomès, Régis and Allen, Christine},
 journal = {Nanomedicine Nanotechnology Biology and Medicine}
}

Nanoparticles are promising drug delivery systems whose selection and optimization can be gainfully conducted by theoretical methods. This review is targeted to experimentalists who are interested in enhancing their time and cost efficiency through the incorporation of theoretical approaches. This review thus begins with a brief overview of theoretical approaches available to the development of contem- porary drug delivery systems. Approaches include solubility parameters, Flory-Huggins theory, analytical predictions of partition coeffi- cients, and molecular simulations. These methods are then compared as they relate to the optimization of drug-material pairs using important performance-related parameters including the size of the delivery particles, their surface properties, and the compatibility of the materials with the drug to be sequestered. Next, this review explores contemporary efforts to optimize a selection of existing nanoparticle platforms, including nanoemulsions, linear and star-shaped block co-polymer micelles, and dendrimers. The review concludes with an outlook on the challenges remaining in the successful application of these theoretical methods to the development of new drug formulations.

@article{
 title = {Molecular basis of proton uptake in single and double mutants of cytochrome c oxidase},
 type = {article},
 year = {2011},
 pages = {234102},
 volume = {23},
 websites = {http://iopscience.iop.org/0953-8984/23/23/234102/},
 month = {6},
 id = {2892868c-414b-3f26-b62c-04d502170c93},
 created = {2011-12-07T04:44:01.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay of long-range electrostatic forces and local structural fluctuations in the control of proton movement and provide a physical explanation for the restoration of proton pumping activity in the double mutant.},
 bibtype = {article},
 author = {Henry, Rowan M and Caplan, David and Fadda, Elisa and Pomès, Régis},
 journal = {J Phys Condens Matter},
 number = {23}
}

Cytochrome c oxidase, the terminal enzyme of the respiratory chain, utilizes the reduction of dioxygen into water to pump protons across the mitochondrial inner membrane. The principal pathway of proton uptake into the enzyme, the D channel, is a 2.5 nm long channel-like cavity named after a conserved, negatively charged aspartic acid (D) residue thought to help recruiting protons to its entrance (D132 in the first subunit of the S. sphaeroides enzyme). The single-point mutation of D132 to asparagine (N), a neutral residue, abolishes enzyme activity. Conversely, replacing conserved N139, one-third into the D channel, by D, induces a decoupled phenotype, whereby oxygen reduction proceeds but not proton pumping. Intriguingly, the double mutant D132N/N139D, which conserves the charge of the D channel, restores the wild-type phenotype. We use molecular dynamics simulations and electrostatic calculations to examine the structural and physical basis for the coupling of proton pumping and oxygen chemistry in single and double N139D mutants. The potential of mean force for the conformational isomerization of N139 and N139D side chains reveals the presence of three rotamers, one of which faces the channel entrance. This out-facing conformer is metastable in the wild-type and in the N139D single mutant, but predominant in the double mutant thanks to the loss of electrostatic repulsion with the carboxylate group of D132. The effects of mutations and conformational isomerization on the pKa of E286, an essential proton-shuttling residue located at the top of the D channel, are shown to be consistent with the electrostatic control of proton pumping proposed recently (Fadda et al 2008 Biochim. Biophys. Acta 1777 277-84). Taken together, these results suggest that preserving the spatial distribution of charges at the entrance of the D channel is necessary to guarantee both the uptake and the relay of protons to the active site of the enzyme. These findings highlight the interplay of long-range electrostatic forces and local structural fluctuations in the control of proton movement and provide a physical explanation for the restoration of proton pumping activity in the double mutant.

@article{
 title = {Statistical convergence of equilibrium properties in simulations of molecular solutes embedded in lipid bilayers},
 type = {article},
 year = {2011},
 volume = {7},
 id = {3d401bab-4c3f-335b-a540-0fc3f61da38c},
 created = {2018-06-08T17:39:27.956Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.956Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {In recent years, atomistic molecular simulations have become a method of choice for studying the interaction of small molecules, peptides, and proteins with biological membranes. Here, we critically examine the statistical convergence of equilibrium properties in molecular simulations of two amino acid side-chain analogs, leucine and arginine, in the presence of a hydrated phospholipid bilayer. To this end, the convergence of the standard binding free energy for the reversible insertion of the solutes in the bilayer is systematically assessed by evaluating dozens of separate sets of umbrella sampling calculations for a total simulation time exceeding 400 μs. We identify rare and abrupt transitions in bilayer structure as a function of solute insertion depth. These transitions correspond to the slow reorganization of ionic interactions involving zwitterionic phospholipid headgroups when the solutes penetrate the lipid-water interface and when arginine is forced through the bilayer center. These rare events are shown to constitute hidden sampling barriers that limit the rate of convergence of equilibrium properties and result in systematic sampling errors. Our analysis demonstrates that the difficulty of attaining convergence for lipid bilayer-embedded solutes has, in general, been drastically underestimated. This information will assist future studies in improving accuracy by selecting a more appropriate reaction coordinate or by focusing computational resources on those regions of the reaction coordinate that exhibit slow convergence of equilibrium properties. © 2011 American Chemical Society.},
 bibtype = {article},
 author = {Neale, C. and Bennett, W.F.D. and Tieleman, D.P. and Pomès, R.},
 doi = {10.1021/ct200316w},
 journal = {Journal of Chemical Theory and Computation},
 number = {12}
}

In recent years, atomistic molecular simulations have become a method of choice for studying the interaction of small molecules, peptides, and proteins with biological membranes. Here, we critically examine the statistical convergence of equilibrium properties in molecular simulations of two amino acid side-chain analogs, leucine and arginine, in the presence of a hydrated phospholipid bilayer. To this end, the convergence of the standard binding free energy for the reversible insertion of the solutes in the bilayer is systematically assessed by evaluating dozens of separate sets of umbrella sampling calculations for a total simulation time exceeding 400 μs. We identify rare and abrupt transitions in bilayer structure as a function of solute insertion depth. These transitions correspond to the slow reorganization of ionic interactions involving zwitterionic phospholipid headgroups when the solutes penetrate the lipid-water interface and when arginine is forced through the bilayer center. These rare events are shown to constitute hidden sampling barriers that limit the rate of convergence of equilibrium properties and result in systematic sampling errors. Our analysis demonstrates that the difficulty of attaining convergence for lipid bilayer-embedded solutes has, in general, been drastically underestimated. This information will assist future studies in improving accuracy by selecting a more appropriate reaction coordinate or by focusing computational resources on those regions of the reaction coordinate that exhibit slow convergence of equilibrium properties. © 2011 American Chemical Society.

@article{
 title = {Systematic design of unimolecular star copolymer micelles using molecular dynamics simulations},
 type = {article},
 year = {2010},
 pages = {5491-5501},
 volume = {6},
 websites = {http://pubs.rsc.org/en/content/articlelanding/2010/sm/c001988g},
 id = {9ffd4b19-4f07-3691-87a2-cce13a95f006},
 created = {2011-12-05T17:36:19.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Star copolymers (SCPs) have recently attracted considerable attention due to their unique applicability in a wide range of biomedical fields. With the intention of rationally designing a stable unimolecular SCP, atomistic molecular dynamics simulations of thirteen SCPs are conducted. The SCPs each have six identical arms of methoxypoly(ethylene glycol)-b-polycaprolactone (MePEGx-b-PCLy) and systematically vary in terms of total molecular weight and ratio of hydrophobic to hydrophilic block length. For all hydrated SCPs, the simulations predict a densely packed hydrophobic PCL core that excludes water and is phase separated from a highly mobile hydrophilic PEG corona. The radii of the hydrophobic PCL core and the PEG blocks are independent of each other and can be predicted over a broad molecular weight range. A linear relationship between the hydration and the molecular weight of the PEG blocks is observed with the average number of water molecules bound per PEG repeat unit within the range of that determined experimentally. As well, a quantitative relationship relates the water accessed surface area of the hydrophobic PCL core to the molecular weights of PCL and PEG moieties. We postulate that the propensity for aggregation of SCPs into multimolecular micelles is correlated with the partial hydration of the hydrophobic core of unimers. Our results suggest that SCPs with a hydrophobic PCL core ≤2 kDa per arm are fully protected from water when the hydrophilic PEG blocks approach 14.6 kDa per arm. We therefore predict that SCPs of this composition yield unimolecular micelles that are thermodynamically stable at low concentrations.},
 bibtype = {article},
 author = {Huynh, Loan and Neale, Chris and Pomès, Régis and Allen, Christine},
 journal = {Soft Matter},
 number = {21}
}

Star copolymers (SCPs) have recently attracted considerable attention due to their unique applicability in a wide range of biomedical fields. With the intention of rationally designing a stable unimolecular SCP, atomistic molecular dynamics simulations of thirteen SCPs are conducted. The SCPs each have six identical arms of methoxypoly(ethylene glycol)-b-polycaprolactone (MePEGx-b-PCLy) and systematically vary in terms of total molecular weight and ratio of hydrophobic to hydrophilic block length. For all hydrated SCPs, the simulations predict a densely packed hydrophobic PCL core that excludes water and is phase separated from a highly mobile hydrophilic PEG corona. The radii of the hydrophobic PCL core and the PEG blocks are independent of each other and can be predicted over a broad molecular weight range. A linear relationship between the hydration and the molecular weight of the PEG blocks is observed with the average number of water molecules bound per PEG repeat unit within the range of that determined experimentally. As well, a quantitative relationship relates the water accessed surface area of the hydrophobic PCL core to the molecular weights of PCL and PEG moieties. We postulate that the propensity for aggregation of SCPs into multimolecular micelles is correlated with the partial hydration of the hydrophobic core of unimers. Our results suggest that SCPs with a hydrophobic PCL core ≤2 kDa per arm are fully protected from water when the hydrophilic PEG blocks approach 14.6 kDa per arm. We therefore predict that SCPs of this composition yield unimolecular micelles that are thermodynamically stable at low concentrations.

@article{
 title = {An iris-like mechanism of pore dilation in the CorA magnesium transport system.},
 type = {article},
 year = {2010},
 pages = {784-792},
 volume = {98},
 websites = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2830438&tool=pmcentrez&rendertype=abstract},
 publisher = {The Biophysical Society},
 institution = {The Hospital for Sick Children, Toronto, Canada.},
 id = {effa6c4f-01b1-3b60-913e-4acf1e4d258e},
 created = {2011-12-05T17:36:23.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Magnesium translocation across cell membranes is essential for numerous physiological processes. Three recently reported crystal structures of the CorA magnesium transport system revealed a surprising architecture, with a bundle of giant alpha-helices forming a 60-A-long pore that extends beyond the membrane before widening into a funnel-shaped cytosolic domain. The presence of divalent cations in putative intracellular regulation sites suggests that these structures correspond to the closed conformation of CorA. To examine the nature of the conduction pathway, we performed 110-ns molecular-dynamics simulations of two of these structures in a lipid bilayer with and without regulatory ions. The results show that a 15-A-long hydrophobic constriction straddling the membrane-cytosol interface constitutes a steric bottleneck whose location coincides with an electrostatic barrier opposing cation translocation. In one of the simulations, structural relaxation after the removal of regulatory ions led to concerted changes in the tilt of the pore helices, resulting in iris-like dilation and spontaneous hydration of the hydrophobic neck. This simple and robust mechanism is consistent with the regulation of pore opening by intracellular magnesium concentration, and explains the unusual architecture of CorA.},
 bibtype = {article},
 author = {Chakrabarti, Nilmadhab and Neale, Chris and Payandeh, Jian and Pai, Emil and Pomès, Régis},
 journal = {Biophysical Journal},
 number = {5}
}

Magnesium translocation across cell membranes is essential for numerous physiological processes. Three recently reported crystal structures of the CorA magnesium transport system revealed a surprising architecture, with a bundle of giant alpha-helices forming a 60-A-long pore that extends beyond the membrane before widening into a funnel-shaped cytosolic domain. The presence of divalent cations in putative intracellular regulation sites suggests that these structures correspond to the closed conformation of CorA. To examine the nature of the conduction pathway, we performed 110-ns molecular-dynamics simulations of two of these structures in a lipid bilayer with and without regulatory ions. The results show that a 15-A-long hydrophobic constriction straddling the membrane-cytosol interface constitutes a steric bottleneck whose location coincides with an electrostatic barrier opposing cation translocation. In one of the simulations, structural relaxation after the removal of regulatory ions led to concerted changes in the tilt of the pore helices, resulting in iris-like dilation and spontaneous hydration of the hydrophobic neck. This simple and robust mechanism is consistent with the regulation of pore opening by intracellular magnesium concentration, and explains the unusual architecture of CorA.

@article{
 title = {Molecular simulations of protein disorder.},
 type = {article},
 year = {2010},
 pages = {269-290},
 volume = {88},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/20453929},
 institution = {Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.},
 id = {7e188fce-4392-34e7-902e-cc51a86815f5},
 created = {2011-12-07T04:42:18.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Protein disorder is abundant in proteomes throughout all kingdoms of life and serves many biologically important roles. Disordered states of proteins are challenging to study experimentally due to their structural heterogeneity and tendency to aggregate. Computer simulations, which are not impeded by these properties, have recently emerged as a useful tool to characterize the conformational ensembles of intrinsically disordered proteins. In this review, we provide a survey of computational studies of protein disorder with an emphasis on the interdisciplinary nature of these studies. The application of simulation techniques to the study of disordered states is described in the context of experimental and bioinformatics approaches. Experimental data can be incorporated into simulations, and simulations can provide predictions for experiment. In this way, simulations have been integrated into the existing methodologies for the study of disordered state ensembles. We provide recent examples of simulations of disordered states from the literature and our own work. Throughout the review, we emphasize important predictions and biophysical understanding made possible through the use of simulations. This review is intended as both an overview and a guide for structural biologists and theoretical biophysicists seeking accurate, atomic-level descriptions of disordered state ensembles.},
 bibtype = {article},
 author = {Rauscher, Sarah and Pomès, Régis},
 journal = {Biochemistry and cell biology Biochimie et biologie cellulaire},
 number = {2}
}

Protein disorder is abundant in proteomes throughout all kingdoms of life and serves many biologically important roles. Disordered states of proteins are challenging to study experimentally due to their structural heterogeneity and tendency to aggregate. Computer simulations, which are not impeded by these properties, have recently emerged as a useful tool to characterize the conformational ensembles of intrinsically disordered proteins. In this review, we provide a survey of computational studies of protein disorder with an emphasis on the interdisciplinary nature of these studies. The application of simulation techniques to the study of disordered states is described in the context of experimental and bioinformatics approaches. Experimental data can be incorporated into simulations, and simulations can provide predictions for experiment. In this way, simulations have been integrated into the existing methodologies for the study of disordered state ensembles. We provide recent examples of simulations of disordered states from the literature and our own work. Throughout the review, we emphasize important predictions and biophysical understanding made possible through the use of simulations. This review is intended as both an overview and a guide for structural biologists and theoretical biophysicists seeking accurate, atomic-level descriptions of disordered state ensembles.

@article{
 title = {Systematic Study of Anharmonic Features in a Principal Component Analysis of Gramicidin A},
 type = {article},
 year = {2010},
 pages = {386-395},
 volume = {98},
 websites = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2814209&tool=pmcentrez&rendertype=abstract},
 publisher = {The Biophysical Society},
 institution = {Molecular Structure and Function Programme, Hospital for Sick Children and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.},
 id = {a20f4d7c-3491-3fbd-86f4-73902ea2a550},
 created = {2011-12-07T04:42:23.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {We use principal component analysis (PCA) to detect functionally interesting collective motions in molecular-dynamics simulations of membrane-bound gramicidin A. We examine the statistical and structural properties of all PCA eigenvectors and eigenvalues for the backbone and side-chain atoms. All eigenvalue spectra show two distinct power-law scaling regimes, quantitatively separating large from small covariance motions. Time trajectories of the largest PCs converge to Gaussian distributions at long timescales, but groups of small-covariance PCs, which are usually ignored as noise, have subdiffusive distributions. These non-Gaussian distributions imply anharmonic motions on the free-energy surface. We characterize the anharmonic components of motion by analyzing the mean-square displacement for all PCs. The subdiffusive components reveal picosecond-scale oscillations in the mean-square displacement at frequencies consistent with infrared measurements. In this regime, the slowest backbone mode exhibits tilting of the peptide planes, which allows carbonyl oxygen atoms to provide surrogate solvation for water and cation transport in the channel lumen. Higher-frequency modes are also apparent, and we describe their vibrational spectra. Our findings expand the utility of PCA for quantifying the essential features of motion on the anharmonic free-energy surface made accessible by atomistic molecular-dynamics simulations.},
 bibtype = {article},
 author = {Kurylowicz, Martin and Yu, Ching-Hsing and Pomès, Régis},
 journal = {Biophysical Journal},
 number = {3}
}

We use principal component analysis (PCA) to detect functionally interesting collective motions in molecular-dynamics simulations of membrane-bound gramicidin A. We examine the statistical and structural properties of all PCA eigenvectors and eigenvalues for the backbone and side-chain atoms. All eigenvalue spectra show two distinct power-law scaling regimes, quantitatively separating large from small covariance motions. Time trajectories of the largest PCs converge to Gaussian distributions at long timescales, but groups of small-covariance PCs, which are usually ignored as noise, have subdiffusive distributions. These non-Gaussian distributions imply anharmonic motions on the free-energy surface. We characterize the anharmonic components of motion by analyzing the mean-square displacement for all PCs. The subdiffusive components reveal picosecond-scale oscillations in the mean-square displacement at frequencies consistent with infrared measurements. In this regime, the slowest backbone mode exhibits tilting of the peptide planes, which allows carbonyl oxygen atoms to provide surrogate solvation for water and cation transport in the channel lumen. Higher-frequency modes are also apparent, and we describe their vibrational spectra. Our findings expand the utility of PCA for quantifying the essential features of motion on the anharmonic free-energy surface made accessible by atomistic molecular-dynamics simulations.

@article{
 title = {Conformational Determinants of Phosphotyrosine Peptides Complexed with the Src SH2 Domain},
 type = {article},
 year = {2010},
 pages = {9},
 volume = {5},
 websites = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2888578&tool=pmcentrez&rendertype=abstract},
 publisher = {Public Library of Science},
 institution = {Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. nachman@hera.med.utoronto.ca},
 id = {1e4a4bc7-4062-3cc7-bc48-1a4e0e84b23f},
 created = {2011-12-07T04:42:26.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA) to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the two-pronged plug two-hole socket model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an -helix. In contrast, a -turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors.},
 bibtype = {article},
 author = {Nachman, Joseph and Gish, Gerry and Virag, Cristina and Pawson, Tony and Pomès, Régis and Pai, Emil},
 editor = {Kobe, Bostjan},
 journal = {PLoS ONE},
 number = {6}
}

The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA) to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the two-pronged plug two-hole socket model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an -helix. In contrast, a -turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors.

@article{
 title = {PagP crystallized from SDS/cosolvent reveals the route for phospholipid access to the hydrocarbon ruler.},
 type = {article},
 year = {2010},
 pages = {1210-1219},
 volume = {18},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/20826347},
 institution = {Division of Cancer Genomics and Proteomics, Ontario Cancer Institute and Campbell Family Cancer Research Institute, 101 College Street, Toronto, ON M5G 1L7, Canada.},
 id = {5007fbad-774f-33ef-ae0a-ff8537264342},
 created = {2011-12-07T04:42:38.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Enzymatic reactions involving bilayer lipids occur in an environment with strict physical and topological constraints. The integral membrane enzyme PagP transfers a palmitoyl group from a phospholipid to lipid A in order to assist Escherichia coli in evading host immune defenses during infection. PagP measures the palmitoyl group with an internal hydrocarbon ruler that is formed in the interior of the eight-stranded antiparallel barrel. The access and egress of the palmitoyl group is thought to take a lateral route from the bilayer phase to the barrel interior. Molecular dynamics, mutagenesis, and a 1.4 A crystal structure of PagP in an SDS 2-methyl-2,4-pentanediol (MPD) cosolvent system reveal that phospholipid access occurs at the crenel present between strands F and G of PagP. In this way, the phospholipid head group can remain exposed to the cell exterior while the lipid acyl chain remains in a predominantly hydrophobic environment as it translocates to the protein interior.},
 bibtype = {article},
 author = {Cuesta-Seijo, Jose Antonio and Neale, Chris and Khan, M Adil and Moktar, Joel and Tran, Christopher D and Bishop, Russell E and Pomès, Régis and Privé, Gilbert G},
 journal = {Structure London England 1993},
 number = {9}
}

Enzymatic reactions involving bilayer lipids occur in an environment with strict physical and topological constraints. The integral membrane enzyme PagP transfers a palmitoyl group from a phospholipid to lipid A in order to assist Escherichia coli in evading host immune defenses during infection. PagP measures the palmitoyl group with an internal hydrocarbon ruler that is formed in the interior of the eight-stranded antiparallel barrel. The access and egress of the palmitoyl group is thought to take a lateral route from the bilayer phase to the barrel interior. Molecular dynamics, mutagenesis, and a 1.4 A crystal structure of PagP in an SDS 2-methyl-2,4-pentanediol (MPD) cosolvent system reveal that phospholipid access occurs at the crenel present between strands F and G of PagP. In this way, the phospholipid head group can remain exposed to the cell exterior while the lipid acyl chain remains in a predominantly hydrophobic environment as it translocates to the protein interior.

@inproceedings{
 title = {Simulated tempering distributed replica sampling: A practical guide to enhanced conformational sampling},
 type = {inproceedings},
 year = {2010},
 volume = {256},
 issue = {1},
 id = {b67c7aa3-302e-3146-8bba-89e8c2353840},
 created = {2018-06-08T17:39:27.542Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.542Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Simulated tempering distributed replica sampling (STDR) is a generalized-ensemble method designed specifically for simulations of large molecular systems on shared and heterogeneous computing platforms [Rauscher, Neale and Pomès (2009) J. Chem. Theor. Comput. 5, 2640]. The STDR algorithm consists of an alternation of two steps: (1) a short molecular dynamics (MD) simulation; and (2) a stochastic temperature jump. Repeating these steps thousands of times results in a random walk in temperature, which allows the system to overcome energetic barriers, thereby enhancing conformational sampling. The aim of the present paper is to provide a practical guide to applying STDR to complex biomolecular systems. We discuss the details of our STDR implementation, which is a highly-parallel algorithm designed to maximize computational efficiency while simultaneously minimizing network communication and data storage requirements. Using a 35-residue disordered peptide in explicit water as a test system, we characterize the efficiency of the STDR algorithm with respect to both diffusion in temperature space and statistical convergence of structural properties. Importantly, we show that STDR provides a dramatic enhancement of conformational sampling compared to a canonical MD simulation. © 2010 IOP Publishing Ltd.},
 bibtype = {inproceedings},
 author = {Rauscher, S. and Pomès, R.},
 doi = {10.1088/1742-6596/256/1/012011},
 booktitle = {Journal of Physics: Conference Series}
}

Simulated tempering distributed replica sampling (STDR) is a generalized-ensemble method designed specifically for simulations of large molecular systems on shared and heterogeneous computing platforms [Rauscher, Neale and Pomès (2009) J. Chem. Theor. Comput. 5, 2640]. The STDR algorithm consists of an alternation of two steps: (1) a short molecular dynamics (MD) simulation; and (2) a stochastic temperature jump. Repeating these steps thousands of times results in a random walk in temperature, which allows the system to overcome energetic barriers, thereby enhancing conformational sampling. The aim of the present paper is to provide a practical guide to applying STDR to complex biomolecular systems. We discuss the details of our STDR implementation, which is a highly-parallel algorithm designed to maximize computational efficiency while simultaneously minimizing network communication and data storage requirements. Using a 35-residue disordered peptide in explicit water as a test system, we characterize the efficiency of the STDR algorithm with respect to both diffusion in temperature space and statistical convergence of structural properties. Importantly, we show that STDR provides a dramatic enhancement of conformational sampling compared to a canonical MD simulation. © 2010 IOP Publishing Ltd.

@article{
 title = {Systematic study of anharmonic features in a principal component analysis of gramicidin A},
 type = {article},
 year = {2010},
 volume = {98},
 id = {7f6de896-5fe9-300d-b766-7c22b85b19b1},
 created = {2018-06-08T17:39:27.690Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.690Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {We use principal component analysis (PCA) to detect functionally interesting collective motions in moleculardynamics simulations of membrane-bound gramicidin A. We examine the statistical and structural properties of all PCA eigenvectors and eigenvalues for the backbone and side-chain atoms. All eigenvalue spectra show two distinct power-law scaling regimes, quantitatively separating large from small covariance motions. Time trajectories of the largest PCs converge to Gaussian distributions at long timescales, but groups of small-covariance PCs, which are usually ignored as noise, have subdiffusive distributions. These non-Gaussian distributions imply anharmonic motions on the free-energy surface. We characterize the anharmonic components of motion by analyzing the mean-square displacement for all PCs. The subdiffusive components reveal picosecond-scale oscillations in the mean-square displacement at frequencies consistent with infrared measurements. In this regime, the slowest backbone mode exhibits tilting of the peptide planes, which allows carbonyl oxygen atoms to provide surrogate solvation for water and cation transport in the channel lumen. Higher-frequency modes are also apparent, and we describe their vibrational spectra. Our findings expand the utility of PCA for quantifying the essential features of motion on the anharmonic free-energy surface made accessible by atomistic molecular-dynamics simulations. © 2010 by the Biophysical Society.},
 bibtype = {article},
 author = {Kurylowicz, M. and Yu, C.-H. and Pomès, R.},
 doi = {10.1016/j.bpj.2009.10.034},
 journal = {Biophysical Journal},
 number = {3}
}

We use principal component analysis (PCA) to detect functionally interesting collective motions in moleculardynamics simulations of membrane-bound gramicidin A. We examine the statistical and structural properties of all PCA eigenvectors and eigenvalues for the backbone and side-chain atoms. All eigenvalue spectra show two distinct power-law scaling regimes, quantitatively separating large from small covariance motions. Time trajectories of the largest PCs converge to Gaussian distributions at long timescales, but groups of small-covariance PCs, which are usually ignored as noise, have subdiffusive distributions. These non-Gaussian distributions imply anharmonic motions on the free-energy surface. We characterize the anharmonic components of motion by analyzing the mean-square displacement for all PCs. The subdiffusive components reveal picosecond-scale oscillations in the mean-square displacement at frequencies consistent with infrared measurements. In this regime, the slowest backbone mode exhibits tilting of the peptide planes, which allows carbonyl oxygen atoms to provide surrogate solvation for water and cation transport in the channel lumen. Higher-frequency modes are also apparent, and we describe their vibrational spectra. Our findings expand the utility of PCA for quantifying the essential features of motion on the anharmonic free-energy surface made accessible by atomistic molecular-dynamics simulations. © 2010 by the Biophysical Society.

@article{
 title = {A solution NMR approach to the measurement of amphiphile immersion depth and orientation in membrane model systems.},
 type = {article},
 year = {2009},
 pages = {6452-6459},
 volume = {131},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/19415935},
 institution = {Department of Chemistry, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, Ontario, Canada, L5L 1C6.},
 id = {f051bb5e-b6c5-3375-9e3c-8a31b4fb07be},
 created = {2011-12-07T04:42:41.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Oxygen and Ni(II) are ideal paramagnetic species for NMR studies of immersion depth since they establish prominent concentration gradients across the membrane-water interface of either bilayers or micelles. Corresponding gradients of paramagnetic shifts and relaxation rates are observed by NMR for membrane embedded amphiphiles. Specifically, upon dissolution of oxygen at a partial pressure of 20 bar or more, (13)C NMR spectra of membrane embedded amphiphiles reveal chemical shift perturbations which depend sensitively on average immersion depth in the membrane. Similarly, depth-dependent enhancements of spin-lattice relaxation rates can be detected by (1)H NMR. Generally, such paramagnetic effects depend both on steric or accessibility factors and on the local concentration of the paramagnet. The steric terms can be factored out by combining paramagnetic rates arising from O(2) and Ni, in the form of a ratio, R(1P)(O(2))/R(1P)(Ni). The natural logarithm of this ratio is shown to depend linearly on immersion depth in a micelle. The analysis is verified using molecular dynamics simulations of dodecylphosphocholine in a detergent micelle, while thorough consideration of the paramagnetic rate data also allows for the determination of the orientation of imipramine in the micelle. Thus, a complete picture of topology arises from this approach which is readily applicable to studies of drugs and amphiphiles in fast-tumbling bicelles, small unilamellar vesicles, and micelles.},
 bibtype = {article},
 author = {Al-Abdul-Wahid, M Sameer and Neale, Chris and Pomès, Régis and Prosser, R Scott},
 journal = {Journal of the American Chemical Society},
 number = {18}
}

Oxygen and Ni(II) are ideal paramagnetic species for NMR studies of immersion depth since they establish prominent concentration gradients across the membrane-water interface of either bilayers or micelles. Corresponding gradients of paramagnetic shifts and relaxation rates are observed by NMR for membrane embedded amphiphiles. Specifically, upon dissolution of oxygen at a partial pressure of 20 bar or more, (13)C NMR spectra of membrane embedded amphiphiles reveal chemical shift perturbations which depend sensitively on average immersion depth in the membrane. Similarly, depth-dependent enhancements of spin-lattice relaxation rates can be detected by (1)H NMR. Generally, such paramagnetic effects depend both on steric or accessibility factors and on the local concentration of the paramagnet. The steric terms can be factored out by combining paramagnetic rates arising from O(2) and Ni, in the form of a ratio, R(1P)(O(2))/R(1P)(Ni). The natural logarithm of this ratio is shown to depend linearly on immersion depth in a micelle. The analysis is verified using molecular dynamics simulations of dodecylphosphocholine in a detergent micelle, while thorough consideration of the paramagnetic rate data also allows for the determination of the orientation of imipramine in the micelle. Thus, a complete picture of topology arises from this approach which is readily applicable to studies of drugs and amphiphiles in fast-tumbling bicelles, small unilamellar vesicles, and micelles.

@article{
 title = {Functional hydration and conformational gating of proton uptake in cytochrome c oxidase},
 type = {article},
 year = {2009},
 keywords = {Amino Acid Substitution,Catalytic Domain,Electron Transport Complex IV,Models: Molecular,Mutagenesis: Site-Directed,Oxidation-Reduction,Protein Conformation,Protons,Recombinant Proteins,Rhodobacter sphaeroides,Thermodynamics,Water},
 pages = {1165-1185},
 volume = {387},
 websites = {http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WK7-4VP66CY-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=bfdf50d77d9dcd9f752ee20536a1785e},
 month = {4},
 id = {52c97e8d-bd51-3fa5-9d68-6e9f8b291473},
 created = {2011-12-07T04:43:53.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {Cytochrome c oxidase couples the reduction of dioxygen to proton pumping against an electrochemical gradient. The D-channel, a 25-A-long cavity, provides the principal pathway for the uptake of chemical and pumped protons. A water chain is thought to mediate the relay of protons via a Grotthuss mechanism through the D-channel, but it is interrupted at N139 in all available crystallographic structures. We use free-energy simulations to examine the proton uptake pathway in the wild type and in single-point mutants N139V and N139A, in which redox and pumping activities are compromised. We present a general approach for the calculation of water occupancy in protein cavities and demonstrate that combining efficient sampling algorithms with long simulation times (hundreds of nanoseconds) is required to achieve statistical convergence of equilibrium properties in the protein interior. The relative population of different conformational and hydration states of the D-channel is characterized. Results shed light on the role of N139 in the mechanism of proton uptake and clarify the physical basis for inactive phenotypes. The conformational isomerization of the N139 side chain is shown to act as a gate controlling the formation of a functional water chain or "proton wire." In the closed state of N139, the spatial distribution of water in the D-channel is consistent with available crystallographic models. However, a metastable state of N139 opens up a narrow bottleneck in which 50% occupancy by a water molecule establishes a proton pathway throughout the D-channel. Results for N139V suggest that blockage of proton uptake resulting from persistent interruption of the water pathway is the cause of this mutant's marginal oxidase activity. In contrast, results for N139A indicate that the D-channel is a continuously hydrated cavity, implying that the decoupling of oxidase activity from proton pumping measured in this mutant is not due to interruption of the proton relay chain.},
 bibtype = {article},
 author = {Henry, Rowan M and Yu, Ching-Hsing and Rodinger, Tomas and Pomès, Régis},
 journal = {J Mol Biol},
 number = {5}
}

Cytochrome c oxidase couples the reduction of dioxygen to proton pumping against an electrochemical gradient. The D-channel, a 25-A-long cavity, provides the principal pathway for the uptake of chemical and pumped protons. A water chain is thought to mediate the relay of protons via a Grotthuss mechanism through the D-channel, but it is interrupted at N139 in all available crystallographic structures. We use free-energy simulations to examine the proton uptake pathway in the wild type and in single-point mutants N139V and N139A, in which redox and pumping activities are compromised. We present a general approach for the calculation of water occupancy in protein cavities and demonstrate that combining efficient sampling algorithms with long simulation times (hundreds of nanoseconds) is required to achieve statistical convergence of equilibrium properties in the protein interior. The relative population of different conformational and hydration states of the D-channel is characterized. Results shed light on the role of N139 in the mechanism of proton uptake and clarify the physical basis for inactive phenotypes. The conformational isomerization of the N139 side chain is shown to act as a gate controlling the formation of a functional water chain or "proton wire." In the closed state of N139, the spatial distribution of water in the D-channel is consistent with available crystallographic models. However, a metastable state of N139 opens up a narrow bottleneck in which 50% occupancy by a water molecule establishes a proton pathway throughout the D-channel. Results for N139V suggest that blockage of proton uptake resulting from persistent interruption of the water pathway is the cause of this mutant's marginal oxidase activity. In contrast, results for N139A indicate that the D-channel is a continuously hydrated cavity, implying that the decoupling of oxidase activity from proton pumping measured in this mutant is not due to interruption of the proton relay chain.

@article{
 title = {Simulated Tempering Distributed Replica Sampling , Virtual Replica Exchange , and Other Generalized-Ensemble Methods for Conformational Sampling},
 type = {article},
 year = {2009},
 pages = {2640-2662},
 volume = {5},
 websites = {http://pubs.acs.org/doi/abs/10.1021/ct900302n},
 id = {32dea757-b033-3e59-82fa-be857f7fca26},
 created = {2011-12-07T19:18:07.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Generalized-ensemble algorithms in temperature space have become popular tools to enhance conformational sampling in biomolecular simulations. A random walk in temperature leads to a corresponding random walk in potential energy, which can be used to cross over energetic barriers and overcome the problem of quasi-nonergodicity. In this paper, we introduce two novel methods: simulated tempering distributed replica sampling (STDR) and virtual replica exchange (VREX). These methods are designed to address the practical issues inherent in the replica exchange (RE), simulated tempering (ST), and serial replica exchange (SREM) algorithms. RE requires a large, dedicated, and homogeneous cluster of CPUs to function efficiently when applied to complex systems. ST and SREM both have the drawback of requiring extensive initial simulations, possibly adaptive, for the calculation of weight factors or potential energy distribution functions. STDR and VREX alleviate the need for lengthy initial simulations, and for synchronization and extensive communication between replicas. Both methods are therefore suitable for distributed or heterogeneous computing platforms. We perform an objective comparison of all five algorithms in terms of both implementation issues and sampling efficiency. We use disordered peptides in explicit water as test systems, for a total simulation time of over 42 μs. Efficiency is defined in terms of both structural convergence and temperature diffusion, and we show that these definitions of efficiency are in fact correlated. Importantly, we find that ST-based methods exhibit faster temperature diffusion and correspondingly faster convergence of structural properties compared to RE-based methods. Within the RE-based methods, VREX is superior to both SREM and RE. On the basis of our observations, we conclude that ST is ideal for simple systems, while STDR is well-suited for complex systems.},
 bibtype = {article},
 author = {Rauscher, Sarah and Neale, Chris},
 journal = {J. Chem. Theory and Comput.}
}

Generalized-ensemble algorithms in temperature space have become popular tools to enhance conformational sampling in biomolecular simulations. A random walk in temperature leads to a corresponding random walk in potential energy, which can be used to cross over energetic barriers and overcome the problem of quasi-nonergodicity. In this paper, we introduce two novel methods: simulated tempering distributed replica sampling (STDR) and virtual replica exchange (VREX). These methods are designed to address the practical issues inherent in the replica exchange (RE), simulated tempering (ST), and serial replica exchange (SREM) algorithms. RE requires a large, dedicated, and homogeneous cluster of CPUs to function efficiently when applied to complex systems. ST and SREM both have the drawback of requiring extensive initial simulations, possibly adaptive, for the calculation of weight factors or potential energy distribution functions. STDR and VREX alleviate the need for lengthy initial simulations, and for synchronization and extensive communication between replicas. Both methods are therefore suitable for distributed or heterogeneous computing platforms. We perform an objective comparison of all five algorithms in terms of both implementation issues and sampling efficiency. We use disordered peptides in explicit water as test systems, for a total simulation time of over 42 μs. Efficiency is defined in terms of both structural convergence and temperature diffusion, and we show that these definitions of efficiency are in fact correlated. Importantly, we find that ST-based methods exhibit faster temperature diffusion and correspondingly faster convergence of structural properties compared to RE-based methods. Within the RE-based methods, VREX is superior to both SREM and RE. On the basis of our observations, we conclude that ST is ideal for simple systems, while STDR is well-suited for complex systems.

@article{
 title = {Simulated tempering distributed replica sampling, virtual replica exchange, and other generalized-ensemble methods for conformational sampling},
 type = {article},
 year = {2009},
 volume = {5},
 id = {47ea4370-9a87-3e18-9219-77b57c784839},
 created = {2018-06-08T17:39:27.678Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.678Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Generalized-ensemble algorithms in temperature space have become popular tools to enhance conformational sampling in biomolecular simulations. A random walk in temperature leads to a corresponding random walk in potential energy, which can be used to cross over energetic barriers and overcome the problem of quasi-nonergodicity. In this paper, we introduce two novel methods: simulated tempering distributed replica sampling (STDR) and virtual replica exchange (VREX). These methods are designed to address the practical issues inherent in the replica exchange (RE), simulated tempering (ST), and serial replica exchange (SREM) algorithms. RE requires a large, dedicated, and homogeneous cluster of CPUs to function efficiently when applied to complex systems. ST and SREM both have the drawback of requiring extensive initial simulations, possibly adaptive, for the calculation of weight factors or potential energy distribution functions. STDR and VREX alleviate the need for lengthy initial simulations, and for synchronization and extensive communication between replicas. Both methods are therefore suitable for distributed or heterogeneous computing platforms. We perform an objective comparison of all five algorithms in terms of both implementation issues and sampling efficiency. We use disordered peptides in explicit water as test systems, for a total simulation time of over 42 μs. Efficiency is defined in terms of both structural convergence and temperature diffusion, and we show that these definitions of efficiency are in fact correlated. Importantly, we find that ST-based methods exhibit faster temperature diffusion and correspondingly faster convergence of structural properties compared to RE-based methods. Within the RE-based methods, VREX is superior to both SREM and RE. On the basis of our observations, we conclude that ST is ideal for simple systems, while STDR is well-suited for complex systems. © 2009 American Chemical Society.},
 bibtype = {article},
 author = {Rauscher, S. and Neale, C. and Pomès, R.},
 doi = {10.1021/ct900302n},
 journal = {Journal of Chemical Theory and Computation},
 number = {10}
}

Generalized-ensemble algorithms in temperature space have become popular tools to enhance conformational sampling in biomolecular simulations. A random walk in temperature leads to a corresponding random walk in potential energy, which can be used to cross over energetic barriers and overcome the problem of quasi-nonergodicity. In this paper, we introduce two novel methods: simulated tempering distributed replica sampling (STDR) and virtual replica exchange (VREX). These methods are designed to address the practical issues inherent in the replica exchange (RE), simulated tempering (ST), and serial replica exchange (SREM) algorithms. RE requires a large, dedicated, and homogeneous cluster of CPUs to function efficiently when applied to complex systems. ST and SREM both have the drawback of requiring extensive initial simulations, possibly adaptive, for the calculation of weight factors or potential energy distribution functions. STDR and VREX alleviate the need for lengthy initial simulations, and for synchronization and extensive communication between replicas. Both methods are therefore suitable for distributed or heterogeneous computing platforms. We perform an objective comparison of all five algorithms in terms of both implementation issues and sampling efficiency. We use disordered peptides in explicit water as test systems, for a total simulation time of over 42 μs. Efficiency is defined in terms of both structural convergence and temperature diffusion, and we show that these definitions of efficiency are in fact correlated. Importantly, we find that ST-based methods exhibit faster temperature diffusion and correspondingly faster convergence of structural properties compared to RE-based methods. Within the RE-based methods, VREX is superior to both SREM and RE. On the basis of our observations, we conclude that ST is ideal for simple systems, while STDR is well-suited for complex systems. © 2009 American Chemical Society.

@article{
 title = {Functional Hydration and Conformational Gating of Proton Uptake in Cytochrome c Oxidase},
 type = {article},
 year = {2009},
 keywords = {distributed replica sampling,free energy simulations,protein hydration,redox-coupled proton pump,water-mediated proton transport},
 volume = {387},
 id = {e1cfe447-5ee7-39b9-ae04-39fb373914d2},
 created = {2018-06-08T17:39:27.872Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.872Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Cytochrome c oxidase couples the reduction of dioxygen to proton pumping against an electrochemical gradient. The D-channel, a 25-Å-long cavity, provides the principal pathway for the uptake of chemical and pumped protons. A water chain is thought to mediate the relay of protons via a Grotthuss mechanism through the D-channel, but it is interrupted at N139 in all available crystallographic structures. We use free-energy simulations to examine the proton uptake pathway in the wild type and in single-point mutants N139V and N139A, in which redox and pumping activities are compromised. We present a general approach for the calculation of water occupancy in protein cavities and demonstrate that combining efficient sampling algorithms with long simulation times (hundreds of nanoseconds) is required to achieve statistical convergence of equilibrium properties in the protein interior. The relative population of different conformational and hydration states of the D-channel is characterized. Results shed light on the role of N139 in the mechanism of proton uptake and clarify the physical basis for inactive phenotypes. The conformational isomerization of the N139 side chain is shown to act as a gate controlling the formation of a functional water chain or "proton wire." In the closed state of N139, the spatial distribution of water in the D-channel is consistent with available crystallographic models. However, a metastable state of N139 opens up a narrow bottleneck in which 50% occupancy by a water molecule establishes a proton pathway throughout the D-channel. Results for N139V suggest that blockage of proton uptake resulting from persistent interruption of the water pathway is the cause of this mutant's marginal oxidase activity. In contrast, results for N139A indicate that the D-channel is a continuously hydrated cavity, implying that the decoupling of oxidase activity from proton pumping measured in this mutant is not due to interruption of the proton relay chain. © 2009 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Henry, R.M. and Yu, C.-H. and Rodinger, T. and Pomès, R.},
 doi = {10.1016/j.jmb.2009.02.042},
 journal = {Journal of Molecular Biology},
 number = {5}
}

Cytochrome c oxidase couples the reduction of dioxygen to proton pumping against an electrochemical gradient. The D-channel, a 25-Å-long cavity, provides the principal pathway for the uptake of chemical and pumped protons. A water chain is thought to mediate the relay of protons via a Grotthuss mechanism through the D-channel, but it is interrupted at N139 in all available crystallographic structures. We use free-energy simulations to examine the proton uptake pathway in the wild type and in single-point mutants N139V and N139A, in which redox and pumping activities are compromised. We present a general approach for the calculation of water occupancy in protein cavities and demonstrate that combining efficient sampling algorithms with long simulation times (hundreds of nanoseconds) is required to achieve statistical convergence of equilibrium properties in the protein interior. The relative population of different conformational and hydration states of the D-channel is characterized. Results shed light on the role of N139 in the mechanism of proton uptake and clarify the physical basis for inactive phenotypes. The conformational isomerization of the N139 side chain is shown to act as a gate controlling the formation of a functional water chain or "proton wire." In the closed state of N139, the spatial distribution of water in the D-channel is consistent with available crystallographic models. However, a metastable state of N139 opens up a narrow bottleneck in which 50% occupancy by a water molecule establishes a proton pathway throughout the D-channel. Results for N139V suggest that blockage of proton uptake resulting from persistent interruption of the water pathway is the cause of this mutant's marginal oxidase activity. In contrast, results for N139A indicate that the D-channel is a continuously hydrated cavity, implying that the decoupling of oxidase activity from proton pumping measured in this mutant is not due to interruption of the proton relay chain. © 2009 Elsevier Ltd. All rights reserved.

@article{
 title = {Calculation of absolute protein-ligand binding free energy using distributed replica sampling},
 type = {article},
 year = {2008},
 keywords = {Algorithms,Bacteriophage T4,Benchmarking,Benzene,Computers,Ligands,Models: Chemical,Molecular Conformation,Muramidase,Protein Binding,Stochastic Processes,Thermodynamics},
 pages = {155102},
 volume = {129},
 websites = {http://scitation.aip.org/getabs/servlet/GetabsServlet?prog=normal&id=JCPSA6000129000015155102000001&idtype=cvips&gifs=yes},
 month = {10},
 id = {aa65cc4a-72c2-3fc8-95df-5f80beed5ea9},
 created = {2011-12-07T04:44:50.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {Distributed replica sampling [T. Rodinger et al., J. Chem. Theory Comput. 2, 725 (2006)] is a simple and general scheme for Boltzmann sampling of conformational space by computer simulation in which multiple replicas of the system undergo a random walk in reaction coordinate or temperature space. Individual replicas are linked through a generalized Hamiltonian containing an extra potential energy term or bias which depends on the distribution of all replicas, thus enforcing the desired sampling distribution along the coordinate or parameter of interest regardless of free energy barriers. In contrast to replica exchange methods, efficient implementation of the algorithm does not require synchronicity of the individual simulations. The algorithm is inherently suited for large-scale simulations using shared or heterogeneous computing platforms such as a distributed network. In this work, we build on our original algorithm by introducing Boltzmann-weighted jumping, which allows moves of a larger magnitude and thus enhances sampling efficiency along the reaction coordinate. The approach is demonstrated using a realistic and biologically relevant application; we calculate the standard binding free energy of benzene to the L99A mutant of T4 lysozyme. Distributed replica sampling is used in conjunction with thermodynamic integration to compute the potential of mean force for extracting the ligand from protein and solvent along a nonphysical spatial coordinate. Dynamic treatment of the reaction coordinate leads to faster statistical convergence of the potential of mean force than a conventional static coordinate, which suffers from slow transitions on a rugged potential energy surface.},
 bibtype = {article},
 author = {Rodinger, Tomas and Howell, P Lynne and Pomès, Régis},
 journal = {The Journal of Chemical Physics},
 number = {15}
}

Distributed replica sampling [T. Rodinger et al., J. Chem. Theory Comput. 2, 725 (2006)] is a simple and general scheme for Boltzmann sampling of conformational space by computer simulation in which multiple replicas of the system undergo a random walk in reaction coordinate or temperature space. Individual replicas are linked through a generalized Hamiltonian containing an extra potential energy term or bias which depends on the distribution of all replicas, thus enforcing the desired sampling distribution along the coordinate or parameter of interest regardless of free energy barriers. In contrast to replica exchange methods, efficient implementation of the algorithm does not require synchronicity of the individual simulations. The algorithm is inherently suited for large-scale simulations using shared or heterogeneous computing platforms such as a distributed network. In this work, we build on our original algorithm by introducing Boltzmann-weighted jumping, which allows moves of a larger magnitude and thus enhances sampling efficiency along the reaction coordinate. The approach is demonstrated using a realistic and biologically relevant application; we calculate the standard binding free energy of benzene to the L99A mutant of T4 lysozyme. Distributed replica sampling is used in conjunction with thermodynamic integration to compute the potential of mean force for extracting the ligand from protein and solvent along a nonphysical spatial coordinate. Dynamic treatment of the reaction coordinate leads to faster statistical convergence of the potential of mean force than a conventional static coordinate, which suffers from slow transitions on a rugged potential energy surface.

@article{
 title = {Electrostatic control of proton pumping in cytochrome c oxidase},
 type = {article},
 year = {2008},
 keywords = {*Electrostatics,Animals,Catalysis,Catalytic Domain,Chemical,Computer Simulation,Electron Transport,Electron Transport Complex IV/chemistry/genetics/,Humans,Kinetics,Mitochondria/*enzymology,Models,Molecular,Mutation,Oxidation-Reduction,Oxygen/*metabolism,Protein Conformation,Proton Pumps/*metabolism,Proton-Motive Force,Reproducibility of Results},
 pages = {277-284},
 volume = {1777},
 websites = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18177731},
 month = {3},
 id = {7c9b1537-085a-35b4-9559-a6607d996d82},
 created = {2011-12-07T04:44:54.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {As part of the mitochondrial respiratory chain, cytochrome c oxidase utilizes the energy produced by the reduction of O2 to water to fuel vectorial proton transport. The mechanism coupling proton pumping to redox chemistry is unknown. Recent advances have provided evidence that each of the four observable transitions in the complex catalytic cycle consists of a similar sequence of events. However, the physico-chemical basis underlying this recurring sequence has not been identified. We identify this recurring pattern based on a comprehensive model of the catalytic cycle derived from the analysis of oxygen chemistry and available experimental evidence. The catalytic cycle involves the periodic repetition of a sequence of three states differing in the spatial distribution of charge in the active site: [0|1], [1|0], and [1|1], where the total charge of heme a and the binuclear center appears on the left and on the right, respectively. This sequence recurs four times per turnover despite differences in the redox chemistry. This model leads to a simple, robust, and reproducible sequence of electron and proton transfer steps and rationalizes the pumping mechanism in terms of electrostatic coupling of proton translocation to redox chemistry. Continuum electrostatic calculations support the proposed mechanism and suggest an electrostatic origin for the decoupled and inactive phenotypes of ionic mutants in the principal proton-uptake pathway.},
 bibtype = {article},
 author = {Fadda, Elisa and Yu, Ching-Hsing and Pomès, Régis},
 journal = {Biochim Biophys Acta},
 number = {3}
}

As part of the mitochondrial respiratory chain, cytochrome c oxidase utilizes the energy produced by the reduction of O2 to water to fuel vectorial proton transport. The mechanism coupling proton pumping to redox chemistry is unknown. Recent advances have provided evidence that each of the four observable transitions in the complex catalytic cycle consists of a similar sequence of events. However, the physico-chemical basis underlying this recurring sequence has not been identified. We identify this recurring pattern based on a comprehensive model of the catalytic cycle derived from the analysis of oxygen chemistry and available experimental evidence. The catalytic cycle involves the periodic repetition of a sequence of three states differing in the spatial distribution of charge in the active site: [0|1], [1|0], and [1|1], where the total charge of heme a and the binuclear center appears on the left and on the right, respectively. This sequence recurs four times per turnover despite differences in the redox chemistry. This model leads to a simple, robust, and reproducible sequence of electron and proton transfer steps and rationalizes the pumping mechanism in terms of electrostatic coupling of proton translocation to redox chemistry. Continuum electrostatic calculations support the proposed mechanism and suggest an electrostatic origin for the decoupled and inactive phenotypes of ionic mutants in the principal proton-uptake pathway.

@article{
 title = {Equilibrium exchange enhances the convergence rate of umbrella sampling},
 type = {article},
 year = {2008},
 websites = {http://linkinghub.elsevier.com/retrieve/pii/S0009261408007975},
 month = {1},
 id = {efab3c22-18e7-321e-a6dc-3673a59f14e0},
 created = {2011-12-07T04:45:01.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {to US and demonstrate how may enhance As our methodology, we utilize distributed function (DRPE) introduced by et al.},
 bibtype = {article},
 author = {Neale, Chris and Rodinger, Tomas and Pomès, Régis},
 journal = {Chemical Physics Letters}
}

to US and demonstrate how may enhance As our methodology, we utilize distributed function (DRPE) introduced by et al.

@article{
 title = {Gauging a hydrocarbon ruler by an intrinsic exciton probe.},
 type = {article},
 year = {2007},
 pages = {4565-4579},
 volume = {46},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/17375935},
 institution = {Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.},
 id = {9334c72b-6e61-3280-a435-55cb0cb9ee7a},
 created = {2011-12-05T17:36:16.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {The structural basis of lipid acyl-chain selection by membrane-intrinsic enzymes is poorly understood because most integral membrane enzymes of lipid metabolism have proven refractory to structure determination; however, robust enzymes from the outer membranes of gram-negative bacteria are now providing a first glimpse at the underlying mechanisms. The methylene unit resolution of the phospholipid:lipid A palmitoyltransferase PagP is determined by the hydrocarbon ruler, a 16-carbon saturated acyl-chain-binding pocket buried within the transmembrane beta-barrel structure. Substitution of Gly88 lining the floor of the hydrocarbon ruler with Ala or Met makes the enzyme select specifically 15- or 12-carbon saturated acyl chains, respectively, indicating that hydrocarbon ruler depth determines acyl-chain selection. However, the Gly88Cys PagP resolution does not diminish linearly because it selects both 14- and 15-carbon saturated acyl chains. We discovered that an exciton, emanating from a buried Tyr26-Trp66 phenol-indole interaction, is extinguished by a local structural perturbation arising from the proximal Gly88Cys PagP sulfhydryl group. Site-specific S-methylation of the single Cys afforded Gly88Cys-S-methyl PagP, which reasserted both the exciton and methylene unit resolution by specifically selecting 13-carbon saturated acyl chains for transfer to lipid A. Unlike the other Gly88 substitutions, the Cys sulfhydryl group recedes from the hydrocarbon ruler floor and locally perturbs the subjacent Tyr26 and Trp66 aromatic rings. The resulting hydrocarbon ruler expansion thus occurs at the exciton's expense and accommodates an extra methylene unit in the selected acyl chain. The hydrocarbon ruler-exciton juxtaposition endows PagP with a molecular gauge for probing the structural basis of lipid acyl-chain selection in a membrane-intrinsic environment.},
 bibtype = {article},
 author = {Khan, M Adil and Neale, Chris and Michaux, Catherine and Pomès, Régis and Privé, Gilbert G and Woody, Robert W and Bishop, Russell E},
 journal = {Biochemistry},
 number = {15}
}

The structural basis of lipid acyl-chain selection by membrane-intrinsic enzymes is poorly understood because most integral membrane enzymes of lipid metabolism have proven refractory to structure determination; however, robust enzymes from the outer membranes of gram-negative bacteria are now providing a first glimpse at the underlying mechanisms. The methylene unit resolution of the phospholipid:lipid A palmitoyltransferase PagP is determined by the hydrocarbon ruler, a 16-carbon saturated acyl-chain-binding pocket buried within the transmembrane beta-barrel structure. Substitution of Gly88 lining the floor of the hydrocarbon ruler with Ala or Met makes the enzyme select specifically 15- or 12-carbon saturated acyl chains, respectively, indicating that hydrocarbon ruler depth determines acyl-chain selection. However, the Gly88Cys PagP resolution does not diminish linearly because it selects both 14- and 15-carbon saturated acyl chains. We discovered that an exciton, emanating from a buried Tyr26-Trp66 phenol-indole interaction, is extinguished by a local structural perturbation arising from the proximal Gly88Cys PagP sulfhydryl group. Site-specific S-methylation of the single Cys afforded Gly88Cys-S-methyl PagP, which reasserted both the exciton and methylene unit resolution by specifically selecting 13-carbon saturated acyl chains for transfer to lipid A. Unlike the other Gly88 substitutions, the Cys sulfhydryl group recedes from the hydrocarbon ruler floor and locally perturbs the subjacent Tyr26 and Trp66 aromatic rings. The resulting hydrocarbon ruler expansion thus occurs at the exciton's expense and accommodates an extra methylene unit in the selected acyl chain. The hydrocarbon ruler-exciton juxtaposition endows PagP with a molecular gauge for probing the structural basis of lipid acyl-chain selection in a membrane-intrinsic environment.

@article{
 title = {Distributed replica sampling},
 type = {article},
 year = {2006},
 keywords = {replica exchange,samping,statistics},
 pages = {725-731},
 volume = {2},
 websites = {http://pubs.acs.org/doi/abs/10.1021/ct050302x},
 id = {5db01c1d-af44-3d09-986a-b80414470faf},
 created = {2011-12-05T17:46:36.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Rodinger, Tomas and Howell, P Lynne and Pomès, Régis},
 journal = {J. Chem. Theory and Comput.}
}

@article{
 title = {Proline and glycine control protein self-organization into elastomeric or amyloid fibrils.},
 type = {article},
 year = {2006},
 pages = {1667-1676},
 volume = {14},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/17098192},
 publisher = {Elsevier},
 institution = {Molecular Structure and Function Programme, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.},
 id = {1e3bec40-1f2b-3c9c-912f-95097f50825a},
 created = {2011-12-07T04:42:30.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Elastin provides extensible tissues, including arteries and skin, with the propensity for elastic recoil, whereas amyloid fibrils are associated with tissue-degenerative diseases, such as Alzheimer's. Although both elastin-like and amyloid-like materials result from the self-organization of proteins into fibrils, the molecular basis of their differing physical properties is poorly understood. Using molecular simulations of monomeric and aggregated states, we demonstrate that elastin-like and amyloid-like peptides are separable on the basis of backbone hydration and peptide-peptide hydrogen bonding. The analysis of diverse sequences, including those of elastin, amyloids, spider silks, wheat gluten, and insect resilin, reveals a threshold in proline and glycine composition above which amyloid formation is impeded and elastomeric properties become apparent. The predictive capacity of this threshold is confirmed by the self-assembly of recombinant peptides into either amyloid or elastin-like fibrils. Our findings support a unified model of protein aggregation in which hydration and conformational disorder are fundamental requirements for elastomeric function.},
 bibtype = {article},
 author = {Rauscher, Sarah and Baud, Stéphanie and Miao, Ming and Keeley, Fred W and Pomès, Régis},
 journal = {Structure London England 1993},
 number = {11}
}

Elastin provides extensible tissues, including arteries and skin, with the propensity for elastic recoil, whereas amyloid fibrils are associated with tissue-degenerative diseases, such as Alzheimer's. Although both elastin-like and amyloid-like materials result from the self-organization of proteins into fibrils, the molecular basis of their differing physical properties is poorly understood. Using molecular simulations of monomeric and aggregated states, we demonstrate that elastin-like and amyloid-like peptides are separable on the basis of backbone hydration and peptide-peptide hydrogen bonding. The analysis of diverse sequences, including those of elastin, amyloids, spider silks, wheat gluten, and insect resilin, reveals a threshold in proline and glycine composition above which amyloid formation is impeded and elastomeric properties become apparent. The predictive capacity of this threshold is confirmed by the self-assembly of recombinant peptides into either amyloid or elastin-like fibrils. Our findings support a unified model of protein aggregation in which hydration and conformational disorder are fundamental requirements for elastomeric function.

@article{
 title = {A Scalable FPGA-based Multiprocessor},
 type = {article},
 year = {2006},
 pages = {111-120},
 volume = {71},
 websites = {http://ieeexplore.ieee.org/lpdocs/epic03/wrapper.htm?arnumber=4020900},
 publisher = {Ieee},
 id = {1ee79b02-2768-351a-83bb-8d845fcfd385},
 created = {2011-12-07T04:42:40.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {It has been shown that a small number of FPGAs can significantly accelerate certain computing tasks by up to two or three orders of magnitude. However, particularly intensive large-scale computing applications, such as molecular dynamics simulations of biological systems, underscore the need for even greater speedups to address relevant length and time scales. In this work, we propose an architecture for a scalable computing machine built entirely using FPGA computing nodes. The machine enables designers to implement large-scale computing applications using a heterogeneous combination of hardware accelerators and embedded microprocessors spread across many FPGAs, all interconnected by a flexible communication network. Parallelism at multiple levels of granularity within an application can be exploited to obtain the maximum computational throughput. By focusing on applications that exhibit a high computation-to-communication ratio, we narrow the extent of this investigation to the development of a suitable communication infrastructure for our machine, as well as an appropriate programming model and design flow for implementing applications. By providing a simple, abstracted communication interface with the objective of being able to scale to thousands of FPGA nodes, the proposed architecture appears to the programmer as a unified, extensible FPGA fabric. A programming model based on the MPI message-passing standard is also presented as a means for partitioning an application into independent computing tasks that can be implemented on our architecture. Finally, we demonstrate the first use of our design flow by developing a simple molecular dynamics simulation application for the proposed machine, which runs on a small platform of development boards},
 bibtype = {article},
 author = {Patel, Arun and Madill, Christopher A and Saldana, Manuel and Comis, Christopher and Pomès, Régis and Chow, Paul},
 journal = {2006 14th Annual IEEE Symposium on FieldProgrammable Custom Computing Machines}
}

It has been shown that a small number of FPGAs can significantly accelerate certain computing tasks by up to two or three orders of magnitude. However, particularly intensive large-scale computing applications, such as molecular dynamics simulations of biological systems, underscore the need for even greater speedups to address relevant length and time scales. In this work, we propose an architecture for a scalable computing machine built entirely using FPGA computing nodes. The machine enables designers to implement large-scale computing applications using a heterogeneous combination of hardware accelerators and embedded microprocessors spread across many FPGAs, all interconnected by a flexible communication network. Parallelism at multiple levels of granularity within an application can be exploited to obtain the maximum computational throughput. By focusing on applications that exhibit a high computation-to-communication ratio, we narrow the extent of this investigation to the development of a suitable communication infrastructure for our machine, as well as an appropriate programming model and design flow for implementing applications. By providing a simple, abstracted communication interface with the objective of being able to scale to thousands of FPGA nodes, the proposed architecture appears to the programmer as a unified, extensible FPGA fabric. A programming model based on the MPI message-passing standard is also presented as a means for partitioning an application into independent computing tasks that can be implemented on our architecture. Finally, we demonstrate the first use of our design flow by developing a simple molecular dynamics simulation application for the proposed machine, which runs on a small platform of development boards

@article{
 title = {A combined NMR and molecular dynamics study of the transmembrane solubility and diffusion rate profile of dioxygen in lipid bilayers},
 type = {article},
 year = {2006},
 pages = {10719-10728},
 volume = {45},
 id = {2c50deae-0647-3863-a121-6b9c44233a8e},
 created = {2011-12-07T04:45:04.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Al-Abdul-Wahid, M Sameer and Yu, Ching-Hsing and Batruch, I and Evanics, F and Pomès, Régis and Prosser, R Scott},
 journal = {Biochemistry}
}

@article{
 title = {Reply to "Comment on acidity of a Cu-bound histidine in the binuclear center of cytochrome c oxidase"},
 type = {article},
 year = {2006},
 volume = {110},
 id = {aa44ce0b-7d6f-3081-9e1a-fa330be0db7d},
 created = {2018-06-08T17:39:27.843Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.843Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 bibtype = {article},
 author = {Fadda, E. and Chakrabarti, N. and Pomès, R.},
 doi = {10.1021/jp0680286},
 journal = {Journal of Physical Chemistry B},
 number = {34}
}

@article{
 title = {Proline and Glycine Control Protein Self-Organization into Elastomeric or Amyloid Fibrils},
 type = {article},
 year = {2006},
 keywords = {PROTEINS},
 volume = {14},
 id = {29e38ff5-1884-3925-bc03-52137cbce73d},
 created = {2018-06-08T17:39:28.106Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.106Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Elastin provides extensible tissues, including arteries and skin, with the propensity for elastic recoil, whereas amyloid fibrils are associated with tissue-degenerative diseases, such as Alzheimer's. Although both elastin-like and amyloid-like materials result from the self-organization of proteins into fibrils, the molecular basis of their differing physical properties is poorly understood. Using molecular simulations of monomeric and aggregated states, we demonstrate that elastin-like and amyloid-like peptides are separable on the basis of backbone hydration and peptide-peptide hydrogen bonding. The analysis of diverse sequences, including those of elastin, amyloids, spider silks, wheat gluten, and insect resilin, reveals a threshold in proline and glycine composition above which amyloid formation is impeded and elastomeric properties become apparent. The predictive capacity of this threshold is confirmed by the self-assembly of recombinant peptides into either amyloid or elastin-like fibrils. Our findings support a unified model of protein aggregation in which hydration and conformational disorder are fundamental requirements for elastomeric function. © 2006 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Rauscher, S. and Baud, S. and Miao, M. and Keeley, FredW. and Pomès, R.},
 doi = {10.1016/j.str.2006.09.008},
 journal = {Structure},
 number = {11}
}

Elastin provides extensible tissues, including arteries and skin, with the propensity for elastic recoil, whereas amyloid fibrils are associated with tissue-degenerative diseases, such as Alzheimer's. Although both elastin-like and amyloid-like materials result from the self-organization of proteins into fibrils, the molecular basis of their differing physical properties is poorly understood. Using molecular simulations of monomeric and aggregated states, we demonstrate that elastin-like and amyloid-like peptides are separable on the basis of backbone hydration and peptide-peptide hydrogen bonding. The analysis of diverse sequences, including those of elastin, amyloids, spider silks, wheat gluten, and insect resilin, reveals a threshold in proline and glycine composition above which amyloid formation is impeded and elastomeric properties become apparent. The predictive capacity of this threshold is confirmed by the self-assembly of recombinant peptides into either amyloid or elastin-like fibrils. Our findings support a unified model of protein aggregation in which hydration and conformational disorder are fundamental requirements for elastomeric function. © 2006 Elsevier Ltd. All rights reserved.

@inproceedings{
 title = {A scalable FPGA-based multiprocessor},
 type = {inproceedings},
 year = {2006},
 id = {d2713381-5515-31a2-a4b7-aa04ec97345f},
 created = {2018-06-08T17:39:28.189Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:28.189Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {It has been shown that a small number of FPGAs can significantly accelerate certain computing tasks by up to two or three orders of magnitude. However, particularly intensive large-scale computing applications, such as molecular dynamics simulations of biological systems, underscore the need for even greater speedups to address relevant length and time scales. In this work, we propose an architecture for a scalable computing machine built entirely using FPGA computing nodes. The machine enables designers to implement largescale computing applications using a heterogeneous combination of hardware accelerators and embedded microprocessors spread across many FPGAs, all interconnected by a flexible communication network. Parallelism at multiple levels of granularity within an application can be exploited to obtain the maximum computational throughput. By focusing on applications that exhibit a high computation- tocommunication ratio, we narrow the extent of this investigation to the development of a suitable communication infrastructure for our machine, as well as an appropriate programming model and design flow for implementing applications. By providing a simple, abstracted communication interface with the objective of being able to scale to thousands of FPGA nodes, the proposed architecture appears to the programmer as a unified, extensible FPGA fabric. A programming model based on the MPI message-passing standard is also presented as a means for partitioning an application into independent computing tasks that can be implemented on our architecture. Finally, we demonstrate the first use of our design flow by developing a simple molecular dynamics simulation application for the proposed machine, which runs on a small platform of development boards. © 2006 IEEE.},
 bibtype = {inproceedings},
 author = {Patel, A. and Madill, C.A. and Saldaña, M. and Comis, C. and Pomès, R. and Chow, P.},
 doi = {10.1109/FCCM.2006.17},
 booktitle = {Proceedings - 14th Annual IEEE Symposium on Field-Programmable Custom Computing Machines, FCCM 2006}
}

It has been shown that a small number of FPGAs can significantly accelerate certain computing tasks by up to two or three orders of magnitude. However, particularly intensive large-scale computing applications, such as molecular dynamics simulations of biological systems, underscore the need for even greater speedups to address relevant length and time scales. In this work, we propose an architecture for a scalable computing machine built entirely using FPGA computing nodes. The machine enables designers to implement largescale computing applications using a heterogeneous combination of hardware accelerators and embedded microprocessors spread across many FPGAs, all interconnected by a flexible communication network. Parallelism at multiple levels of granularity within an application can be exploited to obtain the maximum computational throughput. By focusing on applications that exhibit a high computation- tocommunication ratio, we narrow the extent of this investigation to the development of a suitable communication infrastructure for our machine, as well as an appropriate programming model and design flow for implementing applications. By providing a simple, abstracted communication interface with the objective of being able to scale to thousands of FPGA nodes, the proposed architecture appears to the programmer as a unified, extensible FPGA fabric. A programming model based on the MPI message-passing standard is also presented as a means for partitioning an application into independent computing tasks that can be implemented on our architecture. Finally, we demonstrate the first use of our design flow by developing a simple molecular dynamics simulation application for the proposed machine, which runs on a small platform of development boards. © 2006 IEEE.

@article{
 title = {The sulfogalactose moiety of sulfoglycosphingolipids serves as a mimic of tyrosine phosphate in many recognition processes. Prediction and demonstration of Src homology 2 domain/sulfogalactose binding.},
 type = {article},
 year = {2005},
 pages = {12542-12547},
 volume = {280},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/15634687},
 institution = {Research Institute, The Hospital for Sick Children, Toronto, Ontario M4G 1X8, Canada. cling@sickkids.ca},
 id = {7c598912-8f18-3115-a50e-a1a8a175b3cd},
 created = {2011-12-05T17:36:21.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Multiple ligand co-recognition of 3'-sulfogalactosylceramide (SGC) and sulfotyrosine initiated the comparison of SGC and sulfotyrosine and, subsequently, phosphotyrosine (pY) binding. SGC is a receptor for ligands involved in cell adhesion/microbial pathology. pY forms a Src homology domain 2 recognition motif in intracellular signaling. Using hsp70, anti-SGC, and anti-pY antibodies, ligand binding is retained following phosphate/sulfate and tyrosine/galactose substitution in SGC and sulfate/phosphate exchange in pY. Remarkable lipid-dependent binding to phosphatidylethanolamine-conjugated sulfotyrosine suggests "microenvironmental" modulation of sulfotyrosine-containing receptors, similar to glycosphingolipids. Based on an aryl substrate-bound co-crystal of arylsulfatase A, a sulfogalactose and phosphotyrosine esterase, modeling provides a solvation basis for co-recognition. c-Src/Src homology domain binding confirms our hypothesis, heralding a carbohydrate-based approach to regulation of phosphotyrosine-mediated recognition.},
 bibtype = {article},
 author = {Lingwood, Clifford and Mylvaganam, Murugesapillai and Minhas, Farah and Binnington, Beth and Branch, Donald R and Pomès, Régis},
 journal = {The Journal of Biological Chemistry},
 number = {13}
}

Multiple ligand co-recognition of 3'-sulfogalactosylceramide (SGC) and sulfotyrosine initiated the comparison of SGC and sulfotyrosine and, subsequently, phosphotyrosine (pY) binding. SGC is a receptor for ligands involved in cell adhesion/microbial pathology. pY forms a Src homology domain 2 recognition motif in intracellular signaling. Using hsp70, anti-SGC, and anti-pY antibodies, ligand binding is retained following phosphate/sulfate and tyrosine/galactose substitution in SGC and sulfate/phosphate exchange in pY. Remarkable lipid-dependent binding to phosphatidylethanolamine-conjugated sulfotyrosine suggests "microenvironmental" modulation of sulfotyrosine-containing receptors, similar to glycosphingolipids. Based on an aryl substrate-bound co-crystal of arylsulfatase A, a sulfogalactose and phosphotyrosine esterase, modeling provides a solvation basis for co-recognition. c-Src/Src homology domain binding confirms our hypothesis, heralding a carbohydrate-based approach to regulation of phosphotyrosine-mediated recognition.

@article{
 title = {Acidity of a copper-bound histidine in the binuclear center of cytochrome c oxidase},
 type = {article},
 year = {2005},
 pages = {22629-22640},
 volume = {109},
 id = {b90ce5c6-03ac-3090-9cd2-f9c68ea83c0e},
 created = {2011-12-07T04:44:42.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Fadda, Elisa and Chakrabarti, Nilmadhab and Pomès, Régis},
 journal = {J. Phys. Chem. B}
}

@article{
 title = {Absolute free energy calculations by thermodynamic integration in four spatial dimensions},
 type = {article},
 year = {2005},
 pages = {34104},
 volume = {123},
 websites = {http://scitation.aip.org/getabs/servlet/GetabsServlet?prog=normal&id=JCPSA6000123000003034104000001&idtype=cvips&gifs=yes},
 month = {7},
 id = {96155a24-baca-3f08-beeb-7982c2eb24b9},
 created = {2011-12-07T04:44:44.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {An optimized technique for calculating the excess chemical potential of small molecules in dense liquids and the binding affinity of molecular ligands to biomolecules is reported. In this method, a molecular species is coupled to the system of interest via a nonphysical fourth spatial dimension w through which insertion or extraction can be carried out [R. Pomes, E. Eisenmesser, C. B. Post et al., J. Chem. Phys. 111, 3387 (1999)]. Molecular simulations are used to compute the potential of mean force (PMF) acting on the solute molecule in the fourth dimension. The excess chemical potential of that molecule is obtained as the difference in the PMF between fully coupled and fully decoupled systems. The simplicity, efficiency, and generality of the method are demonstrated for the calculation of the hydration free energies of water and methanol as well as sodium, cesium, and chloride ions. A significant advantage over other methods is that the 4D-PMF approach provides a single effective and general route for decoupling all nonbonded interactions (i.e., both Lennard-Jones and Coulombic) at once for both neutral and charged solutes. Direct calculation of the mean force from thermodynamic integration is shown to be more computationally efficient than calculating the PMF from umbrella sampling. Statistical error analysis suggests a simple strategy for optimizing sampling. The detailed analysis of systematic errors arising from the truncation of Coulombic interactions in a solvent droplet of finite size leads to straightforward corrections to ionic hydration free energies.},
 bibtype = {article},
 author = {Rodinger, Tomas and Howell, P Lynne and Pomès, Régis},
 journal = {The Journal of Chemical Physics},
 number = {3}
}

An optimized technique for calculating the excess chemical potential of small molecules in dense liquids and the binding affinity of molecular ligands to biomolecules is reported. In this method, a molecular species is coupled to the system of interest via a nonphysical fourth spatial dimension w through which insertion or extraction can be carried out [R. Pomes, E. Eisenmesser, C. B. Post et al., J. Chem. Phys. 111, 3387 (1999)]. Molecular simulations are used to compute the potential of mean force (PMF) acting on the solute molecule in the fourth dimension. The excess chemical potential of that molecule is obtained as the difference in the PMF between fully coupled and fully decoupled systems. The simplicity, efficiency, and generality of the method are demonstrated for the calculation of the hydration free energies of water and methanol as well as sodium, cesium, and chloride ions. A significant advantage over other methods is that the 4D-PMF approach provides a single effective and general route for decoupling all nonbonded interactions (i.e., both Lennard-Jones and Coulombic) at once for both neutral and charged solutes. Direct calculation of the mean force from thermodynamic integration is shown to be more computationally efficient than calculating the PMF from umbrella sampling. Statistical error analysis suggests a simple strategy for optimizing sampling. The detailed analysis of systematic errors arising from the truncation of Coulombic interactions in a solvent droplet of finite size leads to straightforward corrections to ionic hydration free energies.

@article{
 title = {Enhancing the accuracy, the efficiency and the scope of free energy simulations},
 type = {article},
 year = {2005},
 keywords = {Algorithms,Biopolymers,Computer Simulation,Energy Transfer,Entropy,Macromolecular Substances,Models: Chemical,Models: Molecular,Thermodynamics},
 pages = {164-170},
 volume = {15},
 month = {4},
 id = {fe249302-3405-3111-835b-1ba538779d9c},
 created = {2011-12-07T04:44:56.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {Many different methods exist for computing free energy changes from molecular simulations. Recent advances have led to improvements in the theoretical framework underlying these calculations, as well as in the accuracy and sampling efficiency of the algorithms. Novel methods combining the advantages afforded by various existing approaches offer promising strategies and open up new perspectives to help elucidate the physical basis of important biological processes.},
 bibtype = {article},
 author = {Rodinger, Tomas and Pomès, Régis},
 journal = {Curr Opin Struct Biol},
 number = {2}
}

Many different methods exist for computing free energy changes from molecular simulations. Recent advances have led to improvements in the theoretical framework underlying these calculations, as well as in the accuracy and sampling efficiency of the algorithms. Novel methods combining the advantages afforded by various existing approaches offer promising strategies and open up new perspectives to help elucidate the physical basis of important biological processes.

@article{
 title = {Structural determinants of proton blockage in aquaporins},
 type = {article},
 year = {2004},
 pages = {493-510},
 volume = {343},
 id = {3f95ae70-1891-306a-bf6e-4f130836e204},
 created = {2011-12-07T04:42:46.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
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 read = {true},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Chakrabarti, Nilmadhab and Roux, Benoît and Pomès, Régis},
 journal = {J. Mol. Biol.}
}

@article{
 title = {Molecular basis of proton blockage in aquaporins},
 type = {article},
 year = {2004},
 pages = {65-74},
 volume = {12},
 id = {ce7b495e-1dd9-37c3-9252-2556368e4a76},
 created = {2011-12-07T04:43:59.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Chakrabarti, Nilmadhab and Tajkhorshid, E and Roux, Benoît and Pomès, Régis},
 journal = {Structure}
}

@article{
 title = {Molecular Basis of Proton Blockage in Aquaporins},
 type = {article},
 year = {2004},
 volume = {12},
 id = {338ac670-a961-3ecf-8553-76aef45371d0},
 created = {2018-06-08T17:39:27.778Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.778Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Water transport channels in membrane proteins of the aquaporin superfamily are impermeable to ions, including H + and OH - . We examine the molecular basis for the blockage of proton translocation through the single-file water chain in the pore of a bacterial aquaporin, GlpF. We compute the reversible thermodynamic work for the two complementary steps of the Grotthuss "hop-and-turn" relay mechanism: consecutive transfers of H + along the hydrogen-bonded chain (hop) and conformational reorganization of the chain (turn). In the absence of H + , the strong preference for the bipolar orientation of water around the two Asn-Pro-Ala (NPA) motifs lining the pore over both unidirectional polarization states of the chain precludes the reorganization of the hydrogen-bonded network. Inversely, translocation of an excess proton in either direction is opposed by a free-energy barrier centered at the NPA region. Both hop and turn steps of proton translocation are opposed by the electrostatic field of the channel.},
 bibtype = {article},
 author = {Chakrabarti, N. and Tajkhorshid, E. and Roux, B. and Pomès, R.},
 doi = {10.1016/j.str.2003.11.017},
 journal = {Structure},
 number = {1}
}

Water transport channels in membrane proteins of the aquaporin superfamily are impermeable to ions, including H + and OH - . We examine the molecular basis for the blockage of proton translocation through the single-file water chain in the pore of a bacterial aquaporin, GlpF. We compute the reversible thermodynamic work for the two complementary steps of the Grotthuss "hop-and-turn" relay mechanism: consecutive transfers of H + along the hydrogen-bonded chain (hop) and conformational reorganization of the chain (turn). In the absence of H + , the strong preference for the bipolar orientation of water around the two Asn-Pro-Ala (NPA) motifs lining the pore over both unidirectional polarization states of the chain precludes the reorganization of the hydrogen-bonded network. Inversely, translocation of an excess proton in either direction is opposed by a free-energy barrier centered at the NPA region. Both hop and turn steps of proton translocation are opposed by the electrostatic field of the channel.

@article{
 title = {Relay and blockage of protons in water chains},
 type = {article},
 year = {2003},
 pages = {1288-1297},
 volume = {8},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Relay+and+blockage+of+protons+in+water+chains&ie=UTF-8&oe=UTF-8},
 id = {9554a361-0e78-3071-b9df-0d977059be8a},
 created = {2011-12-07T04:42:45.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Pomès, Régis and Yu, Ching-Hsing},
 journal = {Frontiers in Bioscience}
}

@article{
 title = {Theoretical study of the structure and dynamic fluctuations of dioxolane-linked gramicidin channels},
 type = {article},
 year = {2003},
 pages = {816-831},
 volume = {84},
 id = {2798de1b-5b13-3334-a6cb-d3444f5ddd97},
 created = {2011-12-07T04:43:40.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
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 bibtype = {article},
 author = {Yu, Ching-Hsing and Cukierman, S and Pomès, Régis},
 journal = {Biophys. J.}
}

@article{
 title = {Functional dynamics of ion channels: Modulation of proton movement by conformational switches},
 type = {article},
 year = {2003},
 pages = {13890-13894},
 volume = {125},
 id = {9099156c-f2ff-3c2e-945f-7bbebea7cf95},
 created = {2011-12-07T04:43:51.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 abstract = {Detailed comparative studies of proton relay in native and chemically modified gramicidin channels provide a unique opportunity to uncover the structural basis of biological proton transport. The function of ion channels hinges on their ability to provide surrogate solvation in narrow pore filters so as to overcome the dielectric barrier presented by biological membranes. In the potassium channel KcsA and in the cation channel gramicidin, permeant selectivity and mobility are determined by the proteinaceous matrix via hydrogen bonding, charge-dipole, and dipole-dipole interactions. In particular, main-chain carbonyl groups in these pore interiors play an essential role in the solvation of alkali ions and of protons. In this study, molecular dynamics simulations reveal how the translocation of H+ is controlled by nanosecond conformational transitions exchanging distorted states of the peptidic backbone in the single-file region of a dioxolane-linked analogue of the gramicidin dimer. These results underline the functional role of channel dynamics and provide a mechanism for the modulation of proton currents by fluctuating dipoles.},
 bibtype = {article},
 author = {Yu, Ching-Hsing and Pomès, Régis},
 journal = {J. Amer. Chem. Soc.}
}

Detailed comparative studies of proton relay in native and chemically modified gramicidin channels provide a unique opportunity to uncover the structural basis of biological proton transport. The function of ion channels hinges on their ability to provide surrogate solvation in narrow pore filters so as to overcome the dielectric barrier presented by biological membranes. In the potassium channel KcsA and in the cation channel gramicidin, permeant selectivity and mobility are determined by the proteinaceous matrix via hydrogen bonding, charge-dipole, and dipole-dipole interactions. In particular, main-chain carbonyl groups in these pore interiors play an essential role in the solvation of alkali ions and of protons. In this study, molecular dynamics simulations reveal how the translocation of H+ is controlled by nanosecond conformational transitions exchanging distorted states of the peptidic backbone in the single-file region of a dioxolane-linked analogue of the gramicidin dimer. These results underline the functional role of channel dynamics and provide a mechanism for the modulation of proton currents by fluctuating dipoles.

@article{
 title = {Kinetic isotope effects of proton transfer in aqueous and methanol containing solutions, and in gramicidin channels},
 type = {article},
 year = {2003},
 pages = {179-190},
 volume = {103},
 id = {e49180b0-3a3c-327a-8fd0-9bc5830d2190},
 created = {2011-12-07T04:43:54.000Z},
 file_attached = {true},
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 bibtype = {article},
 author = {Chernyshev, A and Pomès, Régis and Cukierman, S},
 journal = {Biophys. Chem.}
}

@article{
 title = {Functional Dynamics of Ion Channels: Modulation of Proton Movement by Conformational Switches},
 type = {article},
 year = {2003},
 volume = {125},
 id = {b4148d5f-885b-3cbd-adf6-40bb00db9b55},
 created = {2018-06-08T17:39:27.474Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
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 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Detailed comparative studies of proton relay in native and chemically modified gramicidin channels provide a unique opportunity to uncover the structural basis of biological proton transport. The function of ion channels hinges on their ability to provide surrogate solvation in narrow pore filters so as to overcome the dielectric barrier presented by biological membranes. In the potassium channel KcsA and in the cation channel gramicidin, permeant selectivity and mobility are determined by the proteinaceous matrix via hydrogen bonding, charge-dipole, and dipole-dipole interactions. In particular, main-chain carbonyl groups in these pore interiors play an essential role in the solvation of alkali ions and of protons. In this study, molecular dynamics simulations reveal how the translocation of H + is controlled by nanosecond conformational transitions exchanging distorted states of the peptidic backbone in the single-file region of a dioxolane-linked analogue of the gramicidin dimer. These results underline the functional role of channel dynamics and provide a mechanism for the modulation of proton currents by fluctuating dipoles.},
 bibtype = {article},
 author = {Yu, C.-H. and Pomès, R.},
 doi = {10.1021/ja0353208},
 journal = {Journal of the American Chemical Society},
 number = {45}
}

Detailed comparative studies of proton relay in native and chemically modified gramicidin channels provide a unique opportunity to uncover the structural basis of biological proton transport. The function of ion channels hinges on their ability to provide surrogate solvation in narrow pore filters so as to overcome the dielectric barrier presented by biological membranes. In the potassium channel KcsA and in the cation channel gramicidin, permeant selectivity and mobility are determined by the proteinaceous matrix via hydrogen bonding, charge-dipole, and dipole-dipole interactions. In particular, main-chain carbonyl groups in these pore interiors play an essential role in the solvation of alkali ions and of protons. In this study, molecular dynamics simulations reveal how the translocation of H + is controlled by nanosecond conformational transitions exchanging distorted states of the peptidic backbone in the single-file region of a dioxolane-linked analogue of the gramicidin dimer. These results underline the functional role of channel dynamics and provide a mechanism for the modulation of proton currents by fluctuating dipoles.

@article{
 title = {Molecular mechanism of H+ conduction in the single-file water chain of the gramicidin channel},
 type = {article},
 year = {2002},
 pages = {2304-2316},
 volume = {82},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Molecular+mechanism+of+H++conduction+in+the+single-file+water+chain+of+the+gramicidin+channel&ie=UTF-8&oe=UTF-8},
 id = {eb862530-8f3a-38bb-b2e1-dc759ca5c394},
 created = {2011-12-07T04:44:04.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
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 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
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 private_publication = {false},
 bibtype = {article},
 author = {Pomès, Régis and Roux, Benoît},
 journal = {Biophys. J.}
}

@article{
 title = {A combined molecular dynamics and diffusion model of single proton conduction through gramicidin},
 type = {article},
 year = {2001},
 pages = {12-30},
 volume = {80},
 id = {490f80fc-219b-39d5-bba8-6266e66b6ddb},
 created = {2011-12-07T04:45:03.000Z},
 file_attached = {true},
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 starred = {false},
 authored = {true},
 confirmed = {true},
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 source_type = {article},
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 bibtype = {article},
 author = {Schumaker, M F and Pomès, Régis and Roux, Benoît},
 journal = {Biophys. J.}
}

@article{
 title = {Framework model for single proton conduction through gramicidin},
 type = {article},
 year = {2001},
 volume = {80},
 id = {d59cfe59-f713-38f9-af14-bce55e178478},
 created = {2018-06-08T17:39:27.971Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.971Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {This paper describes a framework model for proton conduction through gramicidin; a model designed to incorporate information from molecular dynamics and use this to predict conductance properties. The state diagram describes both motion of an excess proton within the pore as well as the reorientation of waters within the pore in the absence of an excess proton. The model is constructed as the diffusion limit of a random walk, allowing control over the boundary behavior of trajectories. Simple assumptions about the boundary behavior are made, which allow an analytical solution for the proton current and conductance. This is compared with corresponding expressions from statistical mechanics. The random walk construction allows diffusing trajectories underlying the model to be simulated in a simple way. Details of the numerical algorithm are described.},
 bibtype = {article},
 author = {Schumaker, M.F. and Pomès, R. and Roux, B.},
 doi = {10.1016/S0006-3495(01)75992-9},
 journal = {Biophysical Journal},
 number = {1}
}

This paper describes a framework model for proton conduction through gramicidin; a model designed to incorporate information from molecular dynamics and use this to predict conductance properties. The state diagram describes both motion of an excess proton within the pore as well as the reorientation of waters within the pore in the absence of an excess proton. The model is constructed as the diffusion limit of a random walk, allowing control over the boundary behavior of trajectories. Simple assumptions about the boundary behavior are made, which allow an analytical solution for the proton current and conductance. This is compared with corresponding expressions from statistical mechanics. The random walk construction allows diffusing trajectories underlying the model to be simulated in a simple way. Details of the numerical algorithm are described.

@article{
 title = {A framework model for single proton conductance through gramicidin},
 type = {article},
 year = {2000},
 pages = {2840-2857},
 volume = {79},
 id = {187cc380-5399-37d9-af63-3dfa32b376a8},
 created = {2011-12-07T04:44:48.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
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 private_publication = {false},
 bibtype = {article},
 author = {Schumaker, M F and Pomès, Régis and Roux, Benoît},
 journal = {Biophys. J.}
}

@article{
 title = {Calculating excess chemical potentials using dynamic simulations in the fourth dimension},
 type = {article},
 year = {1999},
 pages = {3387-3395},
 volume = {111},
 id = {01213795-f5df-3641-8981-f63d9b023485},
 created = {2011-12-07T04:44:07.000Z},
 file_attached = {true},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2017-03-28T17:10:06.277Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Pomès, Régis and Eisenmesser, E and Post, C B and Roux, Benoît},
 journal = {J. Chem. Phys.}
}

@article{
 title = {Theoretical studies of the Grotthuss mechanism in biological proton wires},
 type = {article},
 year = {1999},
 volume = {39},
 id = {6fd1b6ae-aadc-3f63-8461-badcd44d251f},
 created = {2018-06-08T17:39:27.398Z},
 file_attached = {false},
 profile_id = {0633c91d-b6d5-3fcd-9fa3-6021f99f2c58},
 last_modified = {2018-06-08T17:39:27.398Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {The structural, dynamic, and thermodynamic properties of proton wires are examined. Detailed molecular aspects of both hop and turn steps of the Grotthuss mechanism for proton conduction along single-file chains of water molecules in model nonpolar pores and in the gramicidin A channel are reviewed, and new simulation results are presented. The Grotthuss mechanism is discussed and analyzed in terms of hydrogen-bonded network structure and connectivity, and the properties of proton wires are contrasted to those of hulk water. General considerations regarding the biological relevance of such studies are proposed.},
 bibtype = {article},
 author = {Pomès, R.},
 doi = {10.1002/ijch.199900044},
 journal = {Israel Journal of Chemistry},
 number = {3-4}
}

The structural, dynamic, and thermodynamic properties of proton wires are examined. Detailed molecular aspects of both hop and turn steps of the Grotthuss mechanism for proton conduction along single-file chains of water molecules in model nonpolar pores and in the gramicidin A channel are reviewed, and new simulation results are presented. The Grotthuss mechanism is discussed and analyzed in terms of hydrogen-bonded network structure and connectivity, and the properties of proton wires are contrasted to those of hulk water. General considerations regarding the biological relevance of such studies are proposed.

@article{
 title = {Structure and dynamics of a proton shuttle in cytochrome c oxidase},
 type = {article},
 year = {1998},
 pages = {255-260},
 volume = {1365},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Structure+and+dynamics+of+a+proton+shuttle+in+cytochrome+c+oxidase&ie=UTF-8&oe=UTF-8},
 id = {4f46d763-e3c5-3e81-aea4-e20148709516},
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 starred = {false},
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 hidden = {false},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Pomès, Régis and Hummer, G and Wikström, M},
 journal = {Biochim. Biophys. Acta}
}

@article{
 title = {Free energy profiles for H+ conduction along hydrogen-bonded chains of water molecules},
 type = {article},
 year = {1998},
 pages = {33-40},
 volume = {75},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Free+energy+profiles+for+H++conduction+along+hydrogen-bonded+chains+of+water+molecules&ie=UTF-8&oe=UTF-8},
 id = {504be2d6-da63-3fd4-9206-53c7f5766739},
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 journal = {Biophys. J.}
}

@article{
 title = {Structure and dynamics of a proton wire: A theoretical study of H+ translocation along the single-file water chain in the gramicidin channel},
 type = {article},
 year = {1996},
 pages = {19-39},
 volume = {71},
 id = {f601dd6e-de39-3d9d-8360-ef81d0f73fe4},
 created = {2011-12-07T04:43:33.000Z},
 file_attached = {true},
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 journal = {Biophys. J.}
}

@article{
 title = {Theoretical study of H+ translocation along a model proton wire},
 type = {article},
 year = {1996},
 pages = {2519-2527},
 volume = {100},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Theoretical+study+of+H++translocation+along+a+model+proton+wire&ie=UTF-8&oe=UTF-8},
 id = {c5ff1ce5-3c7c-30c2-9865-cfde1ed47bf2},
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 hidden = {false},
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 private_publication = {false},
 bibtype = {article},
 author = {Pomès, Régis and Roux, Benoît},
 journal = {J. Phys. Chem.}
}

@article{
 title = {Thermodynamic stability of water molecules in the bacteriorhodopsin proton channel: A moleculer dynamics free energy perturbation study},
 type = {article},
 year = {1996},
 pages = {670-681},
 volume = {71},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Thermodynamic+stability+of+water+molecules+in+the+bacteriorhodopsin+proton+channel:+A+moleculer+dynamics+free+energy+perturbation+study&ie=UTF-8&oe=UTF-8},
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 title = {Quantum effects on the structure and energy of a protonated linear chain of hydrogen-bonded water molecules},
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 pages = {416-424},
 volume = {234},
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 journal = {Chem. Phys. Lett.}
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 title = {Free energy simulations of the HyHEL-10/HEL antibody-antigen complex},
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 pages = {663-675},
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 journal = {Protein Engin.}
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@article{
 title = {Mass and step-length optimization for the calculation of equilibrium properties},
 type = {article},
 year = {1990},
 pages = {425-429},
 volume = {166},
 websites = {http://www.google.com/search?client=safari&rls=en-us&q=Mass+and+step-length+optimization+for+the+calculation+of+equilibrium+properties&ie=UTF-8&oe=UTF-8},
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@article{
 title = {Mass and step length optimization for the calculation of equilibrium properties by molecular dynamics simulation},
 type = {article},
 year = {1990},
 volume = {166},
 id = {ce830c1b-8971-33a5-899a-e06ce49ab027},
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 abstract = {The effectiveness of combining an assumed hydrogen mass of 10 amu with large step lengths of up to 10 fs in molecular dynamics calculations of equilibrium properties of pure water is investigated. Results are evaluated with respect to simulations featuring an H mass of 1 amu and time step of 2 fs. Although the increased mass reduces the rate of sampling of configurations somewhat, this method allows a significant reduction in the computer time needed to calculate structural and thermodynamic properties. © 1990.},
 bibtype = {article},
 author = {Pomès, R. and McCammon, J.A.},
 doi = {10.1016/0009-2614(90)85055-H},
 journal = {Chemical Physics Letters},
 number = {4}
}

The effectiveness of combining an assumed hydrogen mass of 10 amu with large step lengths of up to 10 fs in molecular dynamics calculations of equilibrium properties of pure water is investigated. Results are evaluated with respect to simulations featuring an H mass of 1 amu and time step of 2 fs. Although the increased mass reduces the rate of sampling of configurations somewhat, this method allows a significant reduction in the computer time needed to calculate structural and thermodynamic properties. © 1990.