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A parameterized, continuum electrostatic model for predicting protein pK(a) values.
MedLine Citation:
PMID:  21557315     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Recognizing the limits of trying to achieve chemical accuracy for pK(a) calculations with a purely electrostatic model, we include empirical corrections into the Poisson-Boltzmann solver macroscopic electrostatics with atomic detail (Bashford, Biochemistry 1990;29:10219-10225), to improve the reliability and accuracy of the model. The total number of parameters is kept to a minimum to maximize the robustness of the model for compounds outside of the fitting dataset. The parameters are based on: (a) the electrostatic interaction between functional groups close to the titratable site, (b) the electrostatic work required to desolvate the residue, and (c) the site-to-site interactions. These interactions are straightforward to calculate once the electrostatic field has been solved for each residue using the linearized Poisson-Boltzmann equation and are assumed to be linearly related to the intrinsic pK(a) . Two hundred and eighty-six residues from 30 proteins are used to determine the empirical parameters, which result in a root mean square error (RMSE) of 0.70 for the entire set. Eight proteins with 46 experimentally known values were excluded from the parameterization to test the model. This test set had a RMSE of 1.08. We show that the parameterized model improves the results over other models, although like other models the error is strongly correlated with the degree to which a residue is buried. The parameters themselves indicate that local effects are most important for determining the pK(a) , whereas site-to-site interactions are found to be less significant. Proteins 2011; © 2011 Wiley-Liss, Inc.
Authors:
Steven K Burger; Paul W Ayers
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-1
Journal Detail:
Title:  Proteins     Volume:  -     ISSN:  1097-0134     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-5-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8700181     Medline TA:  Proteins     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Wiley-Liss, Inc.
Affiliation:
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St. West, Hamilton, Ontario L8S 4L8, Canada.
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