Peptide Bond Isomerization in High-Temperature Simulations. Neale, C., Pomès, R., & Garcia, A., E. Journal of Chemical Theory and Computation, 12(4):1989-1999, 2016. ![Peptide Bond Isomerization in High-Temperature Simulations [pdf]](https://bibbase.org/img/filetypes/pdf.svg "pdf")
Paper doi abstract bibtex 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 = {Peptide Bond Isomerization in High-Temperature Simulations},
type = {article},
year = {2016},
pages = {1989-1999},
volume = {12},
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created = {2016-09-12T16:10:18.000Z},
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last_modified = {2017-03-28T17:10:06.277Z},
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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}
}
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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. 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