Improving Docking Results via Reranking of Ensembles of Ligand Poses in Multiple X-ray Protein Conformations with MM-GBSA
Improving Docking Results via Reranking of Ensembles of Ligand Poses in Multiple X-ray Protein Conformations with MM-GBSA
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DOI：
10.1021/ci5003735
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发表时间：
2014-10-01
影响因子：
5.6
通讯作者：
Sherman, W.
中科院分区：
文献类型：
--
作者：
Greenidge, P. A.;Kramer, C.;Sherman, W.
有一种倾向，在文献中的评分功能时，对接程序表现不佳。我们的假设是，现有的评分功能需要加强或开发新的，以提高性能的对接程序的任务，如姿态预测和虚拟筛选。然而，失败可能是由于抽样或评分（或两者的组合），虽然前者往往不太重视。在这项工作中，我们使用GOLD和Glide程序在高质量的数据集上探索姿势预测和结合亲和力估计的失败是否更多地归因于采样或评分。我们表明，正确的姿势（对接功率）的识别可以通过将配体应变到评分函数或rescoring不同的对接姿势与MM-GBSA在后处理步骤的合奏得到改善。我们探索使用非默认对接设置，并发现，增强配体采样也提高了对接功率，再次表明，采样是更多的限制比得分在这项工作中调查的对接程序。在cross-docking计算（对接的配体的noncognate受体结构），我们观察到的姿态排名的准确性显着降低，正如预期的，并已被其他人报道，然而，我们表明，这些替代姿势可能实际上是更互补的配体和刚性受体构象之间，强调刚性治疗受体是一个人为的约束对接问题。我们模拟蛋白质的灵活性，通过使用多个晶体构象的蛋白质，并证明对接结果可以改善与此水平的蛋白质采样。这项工作表明，需要更好的采样对接程序，特别是受体。这项研究还强调了RMSD作为姿势复制质量的唯一仲裁者的变量描述值。结果表明，2埃内的晶体的一个可以显示出显着的差异，在计算的相对蛋白质配体能量的配位体构成。不同姿态的MM-GBSA重新评分克服了由于蛋白质制备和结合位点定义而由对接评分函数经历的姿态排序的一些敏感性。
There is a tendency in the literature to be critical of scoring functions when docking programs perform poorly. The assumption is that existing scoring functions need to be enhanced or new ones developed in order to improve the performance of docking programs for tasks such as pose prediction and virtual screening. However, failures can result from either sampling or scoring (or a combination of the two), although less emphasis tends to be given to the former. In this work, we use the programs GOLD and Glide on a high-quality data set to explore whether failures in pose prediction and binding affinity estimation can be attributable more to sampling or scoring. We show that identification of the correct pose (docking power) can be improved by incorporating ligand strain into the scoring function or rescoring an ensemble of diverse docking poses with MM-GBSA in a postprocessing step. We explore the use of nondefault docking settings and find that enhancing ligand sampling also improves docking power, again suggesting that sampling is more limiting than scoring for the docking programs investigated in this work. In cross-docking calculations (docking a ligand to a noncognate receptor structure) we observe a significant reduction in the accuracy of pose ranking, as expected and has been reported by others; however, we demonstrate that these alternate poses may in fact be more complementary between the ligand and the rigid receptor conformation, emphasizing that treating the receptor rigidly is an artificial constraint on the docking problem. We simulate protein flexibility by the use of multiple crystallographic conformations of a protein and demonstrate that docking results can be improved with this level of protein sampling. This work indicates the need for better sampling in docking programs, especially for the receptor. This study also highlights the variable descriptive value of RMSD as the sole arbiter of pose replication quality. It is shown that ligand poses within 2 angstrom of the crystallographic one can show dramatic differences in calculated relative protein-ligand energies. MM-GBSA rescoring of distinct poses overcomes some of the sensitivities of pose ranking experienced by the docking scoring functions due to protein preparation and binding site definition.