Gschwend D A, Kuntz I D
Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143-0446, USA.
J Comput Aided Mol Des. 1996 Apr;10(2):123-32. doi: 10.1007/BF00402820.
Strategies for computational association of molecular components entail a compromise between configurational exploration and accurate evaluation. Following the work of Meng et al. [Proteins, 17 (1993) 266], we investigate issues related to sampling and optimization in molecular docking within the context of the DOCK program. An extensive analysis of diverse sampling conditions for six receptor-ligand complexes has enabled us to evaluate the tractability and utility of on-the-fly force-field score minimization, as well as the method for configurational exploration. We find that the sampling scheme in DOCK is extremely robust in its ability to produce configurations near to those experimentally observed. Furthermore, despite the heavy resource demands of refinement, the incorporation of a rigid-body, grid-based simplex minimizer directly into the docking process results in a docking strategy that is more efficient at retrieving experimentally observed configurations than docking in the absence of optimization. We investigate the capacity for further performance enhancement by implementing a degeneracy checking protocol aimed at circumventing redundant optimizations of geometrically similar orientations. Finally, we present methods that assist in the selection of sampling levels appropriate to desired result quality and available computational resources.
分子成分的计算关联策略需要在构型探索和精确评估之间进行权衡。继Meng等人的工作[《蛋白质》，17(1993)266]之后，我们在DOCK程序的背景下研究了分子对接中与采样和优化相关的问题。对六个受体-配体复合物的各种采样条件进行的广泛分析，使我们能够评估实时力场评分最小化的可处理性和实用性，以及构型探索的方法。我们发现，DOCK中的采样方案在生成接近实验观察到的构型方面具有极强的稳健性。此外，尽管细化需要大量资源，但将基于网格的刚体单纯形最小化器直接纳入对接过程，会产生一种比无优化对接更有效地检索实验观察到的构型的对接策略。我们通过实施一种旨在规避几何相似取向的冗余优化的简并性检查协议，研究了进一步提高性能的能力。最后，我们提出了有助于选择适合所需结果质量和可用计算资源的采样水平的方法。
