The metadynamics method has been shown to be a valuable tool to study the mechanism of molecular recognition in atomistic detail [Gervasio,F.L.;et al.J.Am.Chem.Soc.2005,127,2600].However,it requires an a priori knowledge of all slow degrees of freedom relevant to the docking/undocking mechanism.Here we investigate a combination of docking/clustering with metadynamics performed with a subset of the necessary degrees of freedom(coarse metadynamics),and show that it provides a full mechanistic insight on the protein-ligand docking mechanism.Moreover,the proposed protocol is able to clearly distinguish between crystallographic and noncrystallographic poses of protein-ligand complexes,and also to find the transition state of the full undocking mechanism,thus giving an indication on the binding free energy.
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机译：事实证明，元动力学方法是研究原子细节分子识别机理的宝贵工具[Gervasio，FL; et al.J.Am.Chem.Soc.2005,127,2600]。先验知识，了解所有与对接/分离对接机制相关的慢自由度。在此，我们研究了对接/聚类与必要的自由度子集（粗亚动力学）进行的元动力学的组合，并显示了它提供了完整的机制此外，所提出的方案能够清楚地区分蛋白质-配体复合物的晶体学姿势和非晶体学姿势，并且能够找到完整的解链机理的过渡状态，从而为结合提供了指示。自由能。
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