BLEEP - Potential of mean force describing protein-ligand interactions: I. Generating potential

We have developed BLEEP (biomolecular ligand energy evaluation protocol), an atomic level potential of mean force (PMF) describing protein-ligand interactions. The pair potentials for BLEEP have been derived from high-resolution X-ray structures of protein-ligand complexes in the Brookhaven Protein Data Bank (PDB), with a careful treatment of homology. The use of a broad variety of protein-ligand structures in the derivation phase gives BLEEP more general applicability than previous potentials, which have been based on limited classes of complexes, and thus represents a significant step forward. We calculate the distance distributions in protein-ligand interactions for all 820 possible pairs that can be chosen from our set of 40 different atom types, including polar hydrogen. We then use a reverse Boltzmann methodology to convert these into energy-like pair potential functions. Two versions of BLEEP are calculated, one including and one excluding interactions between protein and water. The pair potentials are found to have the expected forms; polar and hydrogen bonding interactions show minima at short range, around 3.0 Angstrom, whereas a typical hydrophobic interaction is repulsive at this distance, with values above 4.0 Angstrom being preferred. (C) 1999 John Wiley & Sons, Inc.