Energy functions for protein design I: Efficient and accurate continuum electrostatics and solvation

Abstract

Electrostatics and solvation energies are important for defining protein stability, structural specificity, and molecular recognition. Because these energies are difficult to compute quickly and accurately, they are often ignored or modeled very crudely in computational protein design. To address this problem, we have developed a simple, fast, and accurate approximation for calculating Born radii in the context of protein design calculations. When these approximate Born radii are used with the generalized Born continuum dielectric model, energies calculated by the 10 6 ‐fold slower finite difference Poisson‐Boltzmann model are faithfully reproduced. A similar approach can be used for estimating solvent‐accessible surface areas (SASAs). As an independent test, we show that these approximations can be used to accurately predict the experimentally determined p K a s of >200 ionizable groups from 15 proteins.