Abstract
The MM‐SCP has been applied to predict p__K__~a~ values of titratable residues in wild type and mutants of staphylococcal nuclease (SNase). The calculations were based on crystal structures made available by the Garcia‐Moreno Laboratory. In the mutants, mostly deeply buried hydrophobic residues were replaced with ionizable residues, and thus their p__K__~a~ values could be measured and calculated using various methods. The data set used here consisted of a set of WT SNase for which His p__K__~a~ at several ionic strengths had been measured, a set of mutants for which measured p__K__~a~ were available and a set of 11 mutants for which the measured p__K__~a~ were not known at the time of calculation. For this latter set, blind predictions were submitted to the protein p__K__~a~ cooperative, 2009 workshop at Telluride, where the results of the blind predictions were discussed (the RMSD of the submitted set was 1.10 pH units). The calculations on the structures with known p__K__~a~ indicated that in addition to weaknesses of the method, structural issues were observed that led to larger errors (>1) in p__K__~a~ predictions. For example, different crystallographic conditions or steric clashes can lead to differences in the local environment around the titratable residue, which can produce large differences in the calculated p__K__~a~. To gain further insight into the reliability of the MM‐SCP, p__K__~a~ of an extended set of 54 proteins belonging to several structural classes were carried out. Here some initial results from this study are reported to help place the SNase results in the appropriate context. Proteins 2011. © 2011 Wiley‐Liss, Inc.