Influence of pKa 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 pKa values, which are either computed individually for each ionizable residue or obtained from model compounds. The influence of pKa 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 pKas, pKas derived using a Poisson–Boltzmann approach, and empirically-calculated pKas. Dipole moment predictions that neglect pKa shifts are consistently larger than predictions in which they are included. The importance of pKa shifts are observed to vary with protein size, internal permittivity, and solution pH.