An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics
An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics
复制标题
DOI：
10.1021/ct900262t
复制
发表时间：
2009-10-01
影响因子：
5.5
通讯作者：
Brooks, Charles L., III
中科院分区：
文献类型：
--
作者：
Armen, Roger S.;Chen, Jianhan;Brooks, Charles L., III
在分子对接中加入受体的灵活性可以提高柔性蛋白的检测结果。然而，将明确的全原子灵活性与整个蛋白质链的分子动力学相结合也可能引入显著的误差和“噪声”，从而降低对接精度，并降低评分函数对原生姿态进行排序的能力。我们通过比较几种灵活受体模型在p38 α丝裂原活化蛋白激酶的交叉对接和多受体集合对接中的成功，解决了这个明显的悖论。利用分子动力学（MID）和扭转角分子动力学（TAMD），明确的全原子受体灵活性已被纳入基于charmm的分子对接方法，以改进预测的蛋白质-配体结合几何形状。对这些柔性受体模型进行了评估，并将TAMD采样的准确性和效率与MID采样进行了直接比较。比较了几种柔性受体模型，包括柔性侧链，柔性环，多个柔性主链段，以及整个链的柔性处理。我们发现，虽然像预期的那样，提高对接精度需要包括侧链和一些主链的灵活性，但随着额外和不必要的受体灵活性被纳入构象搜索空间，对接精度也会降低。集成对接结果表明，包含蛋白质柔韧性可以提高与227种活性化合物结合数据的一致性。这一比较还表明，灵活的受体模型丰富了高亲和力化合物的鉴定，而不会显著增加低亲和力化合物的假阳性数量。
Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the successes of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38 alpha mitogen-activated protein kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method using both molecular dynamics (MID) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MID sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that, although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high-affinity compound identification without significantly increasing the number of false positives from low-affinity compounds.