ORIENTATIONAL SAMPLING AND RIGID-BODY MINIMIZATION IN MOLECULAR DOCKING REVISITED - ON-THE-FLY OPTIMIZATION AND DEGENERACY REMOVAL

Strategies for computational association of molecular components entai l a compromise between configurational exploration and accurate evalua tion. Following the work of Meng et al. [Proteins, 17 (1993) 266]: we investigate issues related to sampling and optimization in molecular d ocking within the context of the DOCK program. An extensive analysis o f diverse sampling conditions for six receptor-ligand complexes has en abled us to evaluate the tractability and utility of on-the-fly force- field score minimization, as well as the method for configurational ex ploration. We find that the sampling scheme in DOCK is extremely robus t in its ability to produce configurations near to those experimentall y observed. Furthermore, despite the heavy resource demands of refinem ent? the incorporation of a rigid-body, grid-based simplex minimizer d irectly into the docking process results in a docking strategy that is more efficient at retrieving experimentally observed configurations t han docking in the absence of optimization. We investigate the capacit y for further performance enhancement by implementing a degeneracy che cking protocol aimed at circumventing redundant optimizations of geome trically similar orientations. Finally, we present methods that assist in the selection of sampling levels appropriate to desired result qua lity and available computational resources.