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Empirical prediction of protein pKavalues with residue mutation

A fast, empirical method, Mut‐pKa, is presented for predicting the pKa values of ionizable residues in proteins based on mutation. The method compares the effect of mutating each residue that may act as a hydrogen bond donor or acceptor for the ionizable residue. The energetic effect of each type of mutation, along with a desolvation measure and the overall background charge, is fit against pKa data for histidine and carboxyl residues. A total of 214 residues from 35 different proteins were used in the dataset. Using 11 parameters for each type of ionizable residue, a root mean squared error (RMSE) of 0.78 and 1.12 pH units were obtained for carboxyl and histidines residues, respectively, using leave one out cross validation (LOOCV). The results were particularly promising for buried residues, which had RMSE values of 0.99 and 1.13 for carboxyl and histidine residues, respectively. A number of desolvation measures were tested. The simplest measure, the number of atoms surrounding the residue, was found to work best. The effect of using dynamics was also studied using short molecular dynamics runs, followed by minimization of the structures. Mut‐pKa has significantly fewer parameters than, but similar performance to, other empirical methods. Because of this and the LOOCV results, we believe the model is robust and that overfitting is not a problem. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011