FLEXIBLE DOCKING USING TABU SEARCH AND AN EMPIRICAL ESTIMATE OF BINDING-AFFINITY

This article describes the implementation of a new docking approach. T he method uses a Tabu search methodology to dock flexibly ligand molec ules into rigid receptor structures. It uses an empirical objective fu nction with a small number of physically based terms derived from fitt ing experimental binding affinities for crystallographic complexes. Th is means that docking energies produced by the searching algorithm pro vide direct estimates of the binding affinities of the ligands, The me thod has been tested on 50 ligand-receptor complexes for which the exp erimental binding affinity and binding geometry are known, All water m olecules are removed from the structures and ligand molecules are mini mized in vacuo before docking. The lowest energy geometry produced by the docking protocol is within 1.5 Angstrom root-mean square of the ex perimental binding mode for 86% of the complexes. The lowest energies produced by the docking are in fair agreement with the known free ener gies of binding for the ligands. Proteins 33:367-382, 1998, (C) 1998 W iley-Liss, Inc.