Absolute Binding Free Energies between T4 Lysozyme and 141 Small Molecules: Calculations Based on Multiple Rigid Receptor Configurations

Abstract

We demonstrate the feasibility of estimating protein–ligand binding free energies using multiple rigid receptor configurations. On the basis of T4 lysozyme snapshots extracted from six alchemical binding free energy calculations with a flexible receptor, binding free energies were estimated for a total of 141 ligands. For 24 ligands, the calculations reproduced flexible-receptor estimates with a correlation coefficient of 0.90 and a root-mean-square error of 1.59 kcal/mol. The accuracy of calculations based on Poisson–Boltzmann/surface area implicit solvent was comparable to that of previously reported free energy calculations.