BLEEP?potential of mean force describing protein-ligand interactions: II. Calculation of binding energies and comparison with experimental data

Abstract

We have developed BLEEP (biomolecular ligand energy evaluation protocol), an atomic level potential of mean force (PMF) describing protein–ligand interactions. Here, we present four tests designed to assess different attributes of BLEEP. Calculating the energy of a small hydrogen-bonded complex allows us to compare BLEEP's description of this system with a quantum-chemical description. The results suggest that BLEEP gives an adequate description of hydrogen bonding. A study of the relative energies of various heparin binding geometries for human basic fibroblast growth factor (bFGF) demonstrates that BLEEP performs excellently in identifying low-energy binding modes from decoy conformations for a given protein–ligand complex. We also calculate binding energies for a set of 90 protein–ligand complexes, obtaining a correlation coefficient of 0.74 when compared with experiment. This shows that BLEEP can perform well in the difficult area of ranking the interaction energies of diverse complexes. We also study a set of nine serine proteinase–inhibitor complexes; BLEEP's good performance here illustrates its ability to determine the relative energies of a series of similar complexes. We find that a protocol for incorporating solvation does not improve correlation with experiment. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1177–1185, 1999