DOX: A new computational protocol for accurate prediction of the protein-ligand binding structures
DOX: A new computational protocol for accurate prediction of the protein-ligand binding structures
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DOX：一种新的计算协议，用于准确预测蛋白质-配体结合结构
DOI：
10.1002/jcc.24217
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发表时间：
2016
影响因子：
3
通讯作者：
Wan Jian
中科院分区：
文献类型：
--
作者：
Rao Li;Chi Bo;Ren Yanliang;Li Yongjian;Xu Xin;Wan Jian
分子对接技术已被广泛用于预测蛋白质-配体结合模式，特别是在晶体复合物结构未知的情况下。大多数对接算法能够有效地生成大量可能的结合姿势并对其进行排序。然而，他们很难准确地评估这些姿势并识别最准确的结合结构。在这项研究中，我们首先检查了一些对接程序的性能，基于由15个晶体复合物与他汀类药物组成的测试集，用于人3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）。我们发现，对接程序预测的大多数顶级HMGR-他汀类药物结合位姿在能量上是不稳定的，正如高理论水平计算所揭示的那样，这通常伴随着与相应晶体结合结构的几何参数的较大偏差。随后，我们提出了一个新的计算协议，DOX，基于分子对接，ONIOM，和扩展ONIOM（XO）方法的联合使用，以预测准确的结合结构的蛋白质配体复合物的兴趣。我们的测试结果表明，DOX方案可以有效地预测所有15种HMGR-他汀类晶体复合物的准确几何形状，无一例外。这项研究提出了一个有前途的计算路线，作为一个有效的替代实验之一，朝着预测准确的结合结构，这是所有的性质，功能和机制的蛋白质配体复合物的深入理解的先决条件。© 2015威利期刊公司.
Molecular docking techniques have now been widely used to predict the protein–ligand binding modes, especially when the structures of crystal complexes are not available. Most docking algorithms are able to effectively generate and rank a large number of probable binding poses. However, it is hard for them to accurately evaluate these poses and identify the most accurate binding structure. In this study, we first examined the performance of some docking programs, based on a testing set made of 15 crystal complexes with drug statins for the human 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGR). We found that most of the top ranking HMGR–statin binding poses, predicted by the docking programs, were energetically unstable as revealed by the high theoretical‐level calculations, which were usually accompanied by the large deviations from the geometric parameters of the corresponding crystal binding structures. Subsequently, we proposed a new computational protocol, DOX, based on the joint use of molecular Docking, ONIOM, and eXtended ONIOM (XO) methods to predict the accurate binding structures for the protein–ligand complexes of interest. Our testing results demonstrate that the DOX protocol can efficiently predict accurate geometries for all 15 HMGR‐statin crystal complexes without exception. This study suggests a promising computational route, as an effective alternative to the experimental one, toward predicting the accurate binding structures, which is the prerequisite for all the deep understandings of the properties, functions, and mechanisms of the protein–ligand complexes. © 2015 Wiley Periodicals, Inc.