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

We have developed BLEEP (biomolecular ligand energy evaluation protocol), a n atomic level potential of mean force (PMF) describing protein-ligand inte ractions. The pair potentials for BLEEP have been derived from high-resolut ion 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 v ariety of protein-ligand structures in the derivation phase gives BLEEP mor e general applicability than previous potentials, which have been based on limited classes of complexes, and thus represents a significant step forwar d. We calculate the distance distributions in protein-ligand interactions f or all 820 possible pairs that can be chosen from our set of 40 different a tom types, including polar hydrogen. We then use a reverse Boltzmann method ology to convert these into energy-like pair potential functions. Two versi ons of BLEEP are calculated, one including and one excluding interactions b etween protein and water. The pair potentials are found to have the expecte d forms; polar and hydrogen bonding interactions show minima at short range , around 3.0 Angstrom, whereas a typical hydrophobic interaction is repulsi ve at this distance, with values above 4.0 Angstrom being preferred. (C) 19 99 John Wiley & Sons, Inc.