A statistical approach to the prediction of p K a values in proteins

We propose a simple model for the calculation of p K a values of ionizable residues in proteins. It is based on the premise that the p K a shift of ionizable residues is linearly correlated to the interaction between a particular residue and the local environment created by the surrounding residues. Despite its simplicity, the model displays good prediction performance. Under the sixfold cross test prediction over a data set of 405 experimental p K a values in 73 protein chains with known structures, the root‐mean‐square deviation (RMSD) between the experimental and calculated p K a was found to be 0.77. The accuracy of this model increases with increasing size of the data set: the RMSD is 0.609 for glutamate (the largest data set with 141 sites) and ∼1 pH unit for lysine, with a data set containing 45 sites. Proteins 2007. © 2007 Wiley‐Liss, Inc.