Using polarizable POSSIM force field and fuzzy-border continuum solvent model to calculate pK(a) shifts of protein residues.

Our Fuzzy-Border (FB) continuum solvent model has been extended and modified to produce hydration parameters for small molecules using POlarizable Simulations Second-order Interaction Model (POSSIM) framework with an average error of 0.136 kcal/mol. It was then used to compute pK shifts for carboxylic and basic residues of the turkey ovomucoid third domain (OMTKY3) protein. The average unsigned errors in the acid and base pK values were 0.37 and 0.4 pH units, respectively, versus 0.58 and 0.7 pH units as calculated with a previous version of polarizable protein force field and Poisson Boltzmann continuum solvent. This POSSIM/FB result is produced with explicit refitting of the hydration parameters to the pK values of the carboxylic and basic residues of the OMTKY3 protein; thus, the values of the acidity constants can be viewed as additional fitting target data. In addition to calculating pK shifts for the OMTKY3 residues, we have studied aspartic acid residues of Rnase Sa. This was done without any further refitting of the parameters and agreement with the experimental pK values is within an average unsigned error of 0.65 pH units. This result included the Asp79 residue that is buried and thus has a high experimental pK value of 7.37 units. Thus, the presented model is capable or reproducing pK results for residues in an environment that is significantly different from the solvated protein surface used in the fitting. Therefore, the POSSIM force field and the FB continuum solvent parameters have been demonstrated to be sufficiently robust and transferable. © 2016 Wiley Periodicals, Inc.