ORIENTATIONAL SAMPLING AND RIGID-BODY MINIMIZATION IN MOLECULAR DOCKING

The biological activities of proteins depend on specific molecular rec ognition and binding. Computational methods for predicting binding mod es can facilitate the discovery and design of ligands and yield inform ation on the factors governing complementarity. The DOCK suite of prog rams has been applied to several systems; here, the degree of orientat ional sampling required to reproduce and identify known binding modes, with and without rigid-body energy minimization, is investigated for four complexes. There is a tradeoff between sampling and minimization. The known binding modes can be identified with intensive sampling alo ne (10,000 to 20,000 orientations generated per system) or with modera te sampling combined with minimization. Optimization improves energies significantly, particularly when steric clashes are present, and brin gs many orientations closer to the experimentally observed position. W hether or not minimization is performed, however, sampling must be suf ficient to find at least one structure in the vicinity of the presumed true binding mode. Hybrid approaches combining docking and minimizati on are promising and will become more viable with the use of faster al gorithms and the judicious selection of fewer orientations for minimiz ation. (C) 1993 Wiley-Liss, Inc.