A fast estimate of electrostatic group contributions to the free energy of protein-inhibitor binding

Dissecting ligand-protein binding free energies in individual contributions of protein residues (which are referred to here as 'group contributions') is of significant importance. For example, such contributions could help in estimating the corresponding mutational effects and in studies of drug resistance problems. However, the meaning of group contributions is not always uniquely defined and the approximations for rapid estimates of such contributions are not well developed. In this paper, the nature of group contributions to binding free energy is examined, focusing particularly on electrostatic contributions which are expected to be well behaved. This analysis examines different definitions of group contributions; the 'relaxed' group contributions that represent the change in binding energy upon mutation of the given residue to glycine, and the 'non-relaxed' group contributions that represent the scaled Coulomb interaction between the given residue and the ligand. Both contributions are defined and evaluated by the linear response approximation (LRA) of the PDLD/ S method. The present analysis considers the binding of pepstatin to endothiapepsin and 23 of its mutants as a test case for a neutral ligand. The 'non-relaxed' group contributions of 15 endothiapepsin residues show significant peaks in the 'electrostatic fingerprint'. The residues that contribute to the electrostatic fingerprint are located in the binding site of endothiapepsin. They include the aspartic dyad (Asp32, Asp215) with adjacent residues and the flap region. Twelve of these 15 residues have a heavy atom distance of