Energy Functions for Protein Design: Adjustment with Protein–Protein Complex Affinities, Models for the Unfolded State, and Negative Design of Solubility and Specificity. Pokala, N. & Handel, T. M. Journal of Molecular Biology, 347(1):203–227, March, 2005. ![Energy Functions for Protein Design: Adjustment with Protein–Protein Complex Affinities, Models for the Unfolded State, and Negative Design of Solubility and Specificity [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex The development of the EGAD program and energy function for protein design is described. In contrast to most protein design methods, which require several empirical parameters or heuristics such as patterning of residues or rotamers, EGAD has a minimalist philosophy; it uses very few empirical factors to account for inaccuracies resulting from the use of fixed backbones and discrete rotamers in protein design calculations, and describes the unfolded state, aggregates, and alternative conformers explicitly with physical models instead of fitted parameters. This approach unveils important issues in protein design that are often camouflaged by heuristic-emphasizing methods. Inter-atom energies are modeled with the OPLS-AA all-atom forcefield, electrostatics with the generalized Born continuum model, and the hydrophobic effect with a solvent-accessible surface area-dependent term. Experimental characterization of proteins designed with an unmodified version of the energy function revealed problems with under-packing, stability, aggregation, and structural specificity. Under-packing was addressed by modifying the van der Waals function. By optimizing only three parameters, the effects of \textgreater400 mutations on protein–protein complex formation were predicted to within 1.0kcalmol−1. As an independent test, this modified energy function was used to predict the stabilities of \textgreater1500 mutants to within 1.0kcalmol−1; this required a physical model of the unfolded state that includes more interactions than traditional tripeptide-based models. Solubility and structural specificity were addressed with simple physical approximations of aggregation and conformational equilibria. The complete energy function can design protein sequences that have high levels of identity with their natural counterparts, and have predicted structural properties more consistent with soluble and uniquely folded proteins than the initial designs.
@article{pokala_energy_2005,
title = {Energy {Functions} for {Protein} {Design}: {Adjustment} with {Protein}–{Protein} {Complex} {Affinities}, {Models} for the {Unfolded} {State}, and {Negative} {Design} of {Solubility} and {Specificity}},
volume = {347},
issn = {0022-2836},
shorttitle = {Energy {Functions} for {Protein} {Design}},
url = {http://www.sciencedirect.com/science/article/pii/S002228360401589X},
doi = {10.1016/j.jmb.2004.12.019},
abstract = {The development of the EGAD program and energy function for protein design is described. In contrast to most protein design methods, which require several empirical parameters or heuristics such as patterning of residues or rotamers, EGAD has a minimalist philosophy; it uses very few empirical factors to account for inaccuracies resulting from the use of fixed backbones and discrete rotamers in protein design calculations, and describes the unfolded state, aggregates, and alternative conformers explicitly with physical models instead of fitted parameters. This approach unveils important issues in protein design that are often camouflaged by heuristic-emphasizing methods. Inter-atom energies are modeled with the OPLS-AA all-atom forcefield, electrostatics with the generalized Born continuum model, and the hydrophobic effect with a solvent-accessible surface area-dependent term. Experimental characterization of proteins designed with an unmodified version of the energy function revealed problems with under-packing, stability, aggregation, and structural specificity. Under-packing was addressed by modifying the van der Waals function. By optimizing only three parameters, the effects of {\textgreater}400 mutations on protein–protein complex formation were predicted to within 1.0kcalmol−1. As an independent test, this modified energy function was used to predict the stabilities of {\textgreater}1500 mutants to within 1.0kcalmol−1; this required a physical model of the unfolded state that includes more interactions than traditional tripeptide-based models. Solubility and structural specificity were addressed with simple physical approximations of aggregation and conformational equilibria. The complete energy function can design protein sequences that have high levels of identity with their natural counterparts, and have predicted structural properties more consistent with soluble and uniquely folded proteins than the initial designs.},
language = {en},
number = {1},
urldate = {2020-01-24},
journal = {Journal of Molecular Biology},
author = {Pokala, Navin and Handel, Tracy M.},
month = mar,
year = {2005},
keywords = {EGAD, aggregation, design, protein, stability},
pages = {203--227},
}
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In contrast to most protein design methods, which require several empirical parameters or heuristics such as patterning of residues or rotamers, EGAD has a minimalist philosophy; it uses very few empirical factors to account for inaccuracies resulting from the use of fixed backbones and discrete rotamers in protein design calculations, and describes the unfolded state, aggregates, and alternative conformers explicitly with physical models instead of fitted parameters. This approach unveils important issues in protein design that are often camouflaged by heuristic-emphasizing methods. Inter-atom energies are modeled with the OPLS-AA all-atom forcefield, electrostatics with the generalized Born continuum model, and the hydrophobic effect with a solvent-accessible surface area-dependent term. Experimental characterization of proteins designed with an unmodified version of the energy function revealed problems with under-packing, stability, aggregation, and structural specificity. Under-packing was addressed by modifying the van der Waals function. By optimizing only three parameters, the effects of \\textgreater400 mutations on protein–protein complex formation were predicted to within 1.0kcalmol−1. As an independent test, this modified energy function was used to predict the stabilities of \\textgreater1500 mutants to within 1.0kcalmol−1; this required a physical model of the unfolded state that includes more interactions than traditional tripeptide-based models. Solubility and structural specificity were addressed with simple physical approximations of aggregation and conformational equilibria. The complete energy function can design protein sequences that have high levels of identity with their natural counterparts, and have predicted structural properties more consistent with soluble and uniquely folded proteins than the initial designs.","language":"en","number":"1","urldate":"2020-01-24","journal":"Journal of Molecular Biology","author":[{"propositions":[],"lastnames":["Pokala"],"firstnames":["Navin"],"suffixes":[]},{"propositions":[],"lastnames":["Handel"],"firstnames":["Tracy","M."],"suffixes":[]}],"month":"March","year":"2005","keywords":"EGAD, aggregation, design, protein, stability","pages":"203–227","bibtex":"@article{pokala_energy_2005,\n\ttitle = {Energy {Functions} for {Protein} {Design}: {Adjustment} with {Protein}–{Protein} {Complex} {Affinities}, {Models} for the {Unfolded} {State}, and {Negative} {Design} of {Solubility} and {Specificity}},\n\tvolume = {347},\n\tissn = {0022-2836},\n\tshorttitle = {Energy {Functions} for {Protein} {Design}},\n\turl = {http://www.sciencedirect.com/science/article/pii/S002228360401589X},\n\tdoi = {10.1016/j.jmb.2004.12.019},\n\tabstract = {The development of the EGAD program and energy function for protein design is described. 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