Calculation of amino acid pKaS in a protein from a continuum electrostatic model: Method and sensitivity analysis

We used continuum electrostatic theory to calculate pKas of amino acids in protein. A Green's function formalism, based on a finite‐difference solution to the Poisson–Boltzmann equation for a unit point charge, yields electrostatic potentials that allow calculation of amino acid pKas to an estimated accuracy of tenths of a pKa unit. Improvements over previous methods include the ability to focus the finite difference grid to arbitrarily small grid spacing, an analytical representation of the molecular surface, and a novel procedure to calculate the reaction field potential. Using this method, we performed a sensitivity analysis of calculated pKas in the photosynthetic reaction center. Calculated pKas are most sensitive for residues that are not well‐exposed to solvent. Variations in the parameters of the continuum electrostatic model cause pKa shifts that are larger than the accuracy of the numerical method, but probably not large enough to account for some of the discrepancies between calculated and experimentally measured pKas that have been reported for the reaction center. © 1996 by John Wiley & Sons, Inc.