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Electrostatics of cysteine residues in proteins: Parameterization and validation of a simple model
Author(s) -
Salsbury Freddie R.,
Poole Leslie B.,
Fetrow Jacquelyn S.
Publication year - 2012
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24142
Subject(s) - electrostatics , cysteine , chemistry , static electricity , force field (fiction) , biological system , residue (chemistry) , molecular dynamics , statistical physics , computational chemistry , physics , biochemistry , enzyme , quantum mechanics , biology
One of the most popular and simple models for the calculation of p K a s from a protein structure is the semi‐macroscopic electrostatic model MEAD. This model requires empirical parameters for each residue to calculate p K a s. Analysis of current, widely used empirical parameters for cysteine residues showed that they did not reproduce expected cysteine p K a s; thus, we set out to identify parameters consistent with the CHARMM27 force field that capture both the behavior of typical cysteines in proteins and the behavior of cysteines which have perturbed p K a s. The new parameters were validated in three ways: (1) calculation across a large set of typical cysteines in proteins (where the calculations are expected to reproduce expected ensemble behavior); (2) calculation across a set of perturbed cysteines in proteins (where the calculations are expected to reproduce the shifted ensemble behavior); and (3) comparison to experimentally determined p K a values (where the calculation should reproduce the p K a within experimental error). Both the general behavior of cysteines in proteins and the perturbed p K a in some proteins can be predicted reasonably well using the newly determined empirical parameters within the MEAD model for protein electrostatics. This study provides the first general analysis of the electrostatics of cysteines in proteins, with specific attention paid to capturing both the behavior of typical cysteines in a protein and the behavior of cysteines whose p K a should be shifted, and validation of force field parameters for cysteine residues. Proteins 2012. © 2012 Wiley Periodicals, Inc.