Influence of pK(a) shifts on the calculated dipole moments of proteins.

The protein dipole moment is a low-resolution parameter that characterizes the second-order charge organization of a biomolecule. Theoretical approaches to calculate protein dipole moments rely on pK(a) values, which are either computed individually for each ionizable residue or obtained from model compounds. The influence of pK(a) shifts are evaluated first by comparing calculated and measured dipole moments of β-lactoglobulin. Second, calculations are made on a dataset of 66 proteins from the Protein Data Bank, and average differences are determined between dipole moments calculated with model pK(a)s, pK(a)s derived using a Poisson-Boltzmann approach, and empirically-calculated pK(a)s. Dipole moment predictions that neglect pK(a) shifts are consistently larger than predictions in which they are included. The importance of pK(a) shifts are observed to vary with protein size, internal permittivity, and solution pH.