New and fast statistical-thermodynamic method for computation of protein-ligand binding entropy substantially improves docking accuracy

We present a novel method to estimate the contributions of translational and rotational entropy to protein‐ligand binding affinity. The method is based on estimates of the configurational integral through the sizes of clusters obtained from multiple docking positions. Cluster sizes are defined as the intervals of variation of center of ligand mass and Euler angles in the cluster. Then we suggest a method to consider the entropy of torsional motions. We validate the suggested methods on a set of 135 PDB protein‐ligand complexes by comparing the averaged root‐mean square deviations (RMSD) of the top‐scored ligand docked positions, accounting and not accounting for entropy contributions, relative to the experimentally determined positions. We demonstrate that the method increases docking accuracy by 10–21% when used in conjunction with the AutoDock docking program, thus reducing the percent of incorrectly docked ligands by 1.4‐fold to four‐fold, so that in some cases the percent of ligands correctly docked to within an RMSD of 2 Å is above 90%. We show that the suggested method to account for entropy of relative motions is identical to the method based on the Monte Carlo integration over intervals of variation of center of ligand mass and Euler angles in the cluster. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1089–1095, 2005