Document Type

Article

Publication Date

12-2011

Publication Title

Proteins: Structure, Function, and Bioinformatics

Volume

79

Issue

12

Publisher

Wiley

Abstract

Accurate predictions of pKa values of titratable groups require taking into account all relevant processes associated with the ionization/deionization. Frequently, however, the ionization does not involve significant structural changes and the dominating effects are purely electrostatic in origin allowing accurate predictions to be made based on the electrostatic energy difference between ionized and neutral forms alone using a static structure. On another hand, if the change of the charge state is accompanied by a structural reorganization of the target protein, then the relevant conformational changes have to be taken into account in the pKa calculations. Here we report a hybrid approach that first predicts the titratable groups, which ionization is expected to cause conformational changes, termed “problematic” residues, then applies a special protocol on them, while the rest of the pKa’s are predicted with rigid backbone approach as implemented in multi-conformation continuum electrostatics (MCCE) method. The backbone representative conformations for “problematic” groups are generated with either molecular dynamics simulations with charged and uncharged amino acid or with ab-initio local segment modeling. The corresponding ensembles are then used to calculate the pKa of the “problematic” residues and then the results are averaged.

Comments

This manuscript has been published in the journal Proteins: Structure, Function, and Bioinformatics. Please find the published version here (note that a subscription is necessary to access this version):

http://onlinelibrary.wiley.com/doi/10.1002/prot.23097/abstract

Wiley holds the copyright in this article.

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