Armen Roger S, Chen Jianhan, Brooks Charles L
Department of Chemistry, 930 N. University Ave, University of Michigan, Ann Arbor, MI 48109.
J Chem Theory Comput. 2009 Oct 13;5(10):2909-2923. doi: 10.1021/ct900262t.
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 success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) 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 MD 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 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.
将受体灵活性纳入分子对接应能改善柔性蛋白的对接结果。然而，对整个蛋白质链采用分子动力学纳入明确的全原子灵活性，也可能引入显著误差和“噪声”，从而降低对接准确性，并削弱评分函数对类似天然构象进行排序的能力。我们通过比较几种柔性受体模型在p38α丝裂原活化蛋白（MAP）激酶的交叉对接和多受体整体对接中的成功率，来解决这一明显的矛盾。已使用分子动力学（MD）和扭转角分子动力学（TAMD）将明确的全原子受体灵活性纳入基于CHARMM的分子对接方法（CDOCKER），以优化预测的蛋白质-配体结合几何结构。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MD采样直接进行了比较。比较了几种柔性受体模型，包括柔性侧链、柔性环、多个柔性主链片段以及将整个链视为柔性的情况。我们发现，正如预期的那样，虽然为提高对接准确性需要包括侧链和一些主链灵活性，但随着构象搜索空间中纳入额外且不必要的受体灵活性，对接准确性也会降低。整体对接结果表明，纳入蛋白质灵活性可提高与227种活性化合物结合数据的一致性。这种比较还表明，柔性受体模型在不显著增加低亲和力化合物假阳性数量的情况下，丰富了高亲和力化合物的识别。
