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

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. (C) 1999 John Wiley & Sons, Inc.