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Electrostatics of cysteine residues in proteins: Parameterization and validation of a simple model

Fetrow, Jacquelyn S.

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abstract
One of the most popular and simple models for the calculation of pKas from a protein structure is the semi-macroscopic electrostatic model MEAD. This model requires empirical parameters for each residue to calculate pKas. Analysis of current, widely used empirical parameters for cysteine residues showed that they did not reproduce expected cysteine pKas; 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 pKas. 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 pKa values (where the calculation should reproduce the pKa within experimental error). Both the general behavior of cysteines in proteins and the perturbed pKa 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 pKa should be shifted, and validation of force field parameters for cysteine residues.
description
This is a preprint version; the version of record is available at http://dx.doi.org/10.1002/prot.24142.
subject
MEAD electrostatics model
cysteine pKa calculations
cysteine sulfenic acid
citation
11 (issue)
80 (volume)
contributor
Salsbury, Freddie R. (author)
Poole, Leslie B. (author)
Fetrow, Jacquelyn S. (author)
date
2014-01-10T21:00:04Z (accessioned)
2014-01-10T21:00:04Z (available)
2012 (issued)
identifier
Salsbury, F.R., Jr.; Poole, L.B.; Fetrow, J.S. (2012). "Electrostatics of cysteine residues in proteins: Parameterization and validation of a simple model." Proteins, 80(11):2583-2591. Available at http://dx.doi.org/10.1002/prot.24142. (citation)
http://hdl.handle.net/10339/39105 (uri)
http://dx.doi.org/10.1002/prot.24142 (uri)
publisher
Wiley-Blackwell
source
Proteins: Structure, Function, and Bioinformatics
title
Electrostatics of cysteine residues in proteins: Parameterization and validation of a simple model
type
Article

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