Use of pair potentials across protein interfaces in screening predicted docked complexes

Empirical residue-residue pair potentials are used to screen possible compl exes for protein-protein dockings. A correct docking is defined as a comple x with not more than 2.5 Angstrom root-mean-square distance from the known experimental structure. The complexes were generated by "ftdock" (Gabb et a l. J Mol Biol 1997;272:106-120) that ranks using shape complementarity. The complexes studied were 5 enzyme-inhibitors and 2 antibody-antigens, starti ng from the unbound crystallographic coordinates, with a further 2 antibody -antigens where the antibody was from the bound crystallographic complex. T he pair potential functions tested were derived both from observed intramol ecular pairings in a database of nonhomologous protein domains, and from ob served intermolecular pairings across the interfaces in sets of nonhomologo us heterodimers and homodimers. Out of various alternate strategies, we fou nd the optimal method used a mole-fraction calculated random model from the intramolecular pairings. For all the systems, a correct docking was placed within the top 12% of the pair potential score ranked complexes. A combine d strategy was developed that incorporated "multidock," a side-chain refine ment algorithm (Jackson et al. J Mol Biol 1998;276:265-285). This placed a correct docking within the top 5 complexes for enzyme-inhibitor systems, an d within the top 40 complexes for antibody-antigen systems. (C) 1999 Wiley- Liss, Inc.