Flexible protein-ligand docking by global energy optimization in internal coordinates

Abstract

Eight protein-ligand complexes were simulated by using global optimization of a complex energy function, including solvation, surface tension, and side-chain entropy in the internal coordinate space of the flexible ligand and the receptor side chains [Abagyan, R.A., Totrov, M.M. J. Mol. Biol. 235: 983-1002, 1994]. The procedure uses two types of efficient random moves, a pseudobrownian positional move [Abagyan, R.A., Totrov, M.M., Kuznetsov, D.A. J. Comp. Chem. 15:488-506, 1994] and a Biased-Probability multitorsion move [Abagyan, R.A., Totrov, M.M. J. Mol. Biol. 235: 983-1002, 1994], each accompanied by full local energy minimization. The best docking solutions were further ranked according to the interaction energy, which included intramolecular deformation energies of both receptor and ligand, the interaction energy, surface tension, side-chain entropic contribution, and an electrostatic term evaluated as a boundary element solution of the Poisson equation with the molecular surface as a dielectric boundary. The geometrical accuracy of the docking solutions ranged from 30% to 70% according to the relative displacement error measure at a 1.5 A scale. Similar results were obtained when the explicit receptor atoms were replaced with a grid potential.