Department of Computational Science, Graduate School of System Informatics, Kobe University , 1-1 Rokkodai, Nada, Kobe, Hyogo 657-8501, Japan.
J Chem Inf Model. 2017 Apr 24;57(4):742-756. doi: 10.1021/acs.jcim.6b00791. Epub 2017 Apr 7.
Protein flexibility is a major hurdle in current structure-based virtual screening (VS). In spite of the recent advances in high-performance computing, protein-ligand docking methods still demand tremendous computational cost to take into account the full degree of protein flexibility. In this context, ensemble docking has proven its utility and efficiency for VS studies, but it still needs a rational and efficient method to select and/or generate multiple protein conformations. Molecular dynamics (MD) simulations are useful to produce distinct protein conformations without abundant experimental structures. In this study, we present a novel strategy that makes use of cosolvent-based molecular dynamics (CMD) simulations for ensemble docking. By mixing small organic molecules into a solvent, CMD can stimulate dynamic protein motions and induce partial conformational changes of binding pocket residues appropriate for the binding of diverse ligands. The present method has been applied to six diverse target proteins and assessed by VS experiments using many actives and decoys of DEKOIS 2.0. The simulation results have revealed that the CMD is beneficial for ensemble docking. Utilizing cosolvent simulation allows the generation of druggable protein conformations, improving the VS performance compared with the use of a single experimental structure or ensemble docking by standard MD with pure water as the solvent.
蛋白质的柔性是当前基于结构的虚拟筛选（VS）的主要障碍。尽管最近在高性能计算方面取得了进展，但蛋白质-配体对接方法仍然需要巨大的计算成本来考虑蛋白质的全部柔性。在这种情况下，集合对接已被证明对 VS 研究具有实用性和效率，但仍需要一种合理且高效的方法来选择和/或生成多种蛋白质构象。分子动力学（MD）模拟对于产生不同的蛋白质构象而无需大量实验结构非常有用。在这项研究中，我们提出了一种新策略，利用基于共溶剂的分子动力学（CMD）模拟进行集合对接。通过将小分子有机分子混入溶剂中，CMD 可以刺激蛋白质的动态运动，并诱导结合口袋残基的部分构象变化，从而适合多种配体的结合。本方法已应用于六个不同的靶蛋白，并通过使用 DEKOIS 2.0 的许多活性和诱饵的 VS 实验进行了评估。模拟结果表明，CMD 有利于集合对接。与使用单一实验结构或标准 MD 与纯水作为溶剂的集合对接相比，利用共溶剂模拟可以生成可成药的蛋白质构象，从而提高 VS 性能。
