Institute for Protein Research, Osaka University, Osaka, Japan.
Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Comput Chem. 2020 Jun 30;41(17):1606-1615. doi: 10.1002/jcc.26203. Epub 2020 Apr 8.
Multicanonical molecular dynamics based dynamic docking was used to exhaustively search the configurational space of an inhibitor binding to the N-terminal domain of heat-shock protein 90 (Hsp90). The obtained structures at 300 K cover a wide structural ensemble, with the top two clusters ranked by their free energy coinciding with the native binding site. The representative structure of the most stable cluster reproduced the experimental binding configuration, but an interesting conformational change in Hsp90 could be observed. The combined effects of solvation and ligand binding shift the equilibrium from a preferred loop-in conformation in the unbound state to an α-helical one in the bound state for the flexible lid region of Hsp90. Thus, our dynamic docking method is effective at predicting the native binding site while exhaustively sampling a wide configurational space, modulating the protein structure upon binding.
多正则化分子动力学的动态对接被用来彻底搜索抑制剂与热休克蛋白 90（Hsp90）N 端结构域结合的构象空间。在 300K 下获得的结构覆盖了一个广泛的结构整体，根据自由能排列的前两个簇与天然结合位点一致。最稳定簇的代表性结构再现了实验结合构象，但可以观察到 Hsp90 中的一个有趣的构象变化。溶剂化和配体结合的综合效应将平衡从无结合状态下优选的环内构象转移到结合状态下的 Hsp90 柔性盖区域的α-螺旋构象。因此，我们的动态对接方法在彻底采样广泛构象空间的同时有效地预测了天然结合位点，调节了结合时的蛋白质结构。
