Calculations of the Absolute Free Energy, Enthalpy, and Entropy of Drug Binding Using Different Potential Models

The sensitivity of the free energy, enthalpy, and entropy of ligand binding to variations in the water, protein, and ligand potentials was determined. Nine protein ligand systems with four different proteins were used with four different potential models. Good accuracy of the free energy was achieved for a number of the models, but the enthalpy and entropy changes were far less accurate. A simple scaling of the ligand-water and ligand-protein dispersion interactions showed improved entropies and enthalpies of binding. Further improvements might require ligand potentials specifically parametrized for use with a more optimized water model.