Enhancing Sampling of Water Rehydration on Ligand Binding: A Comparison of Techniques.
Enhancing Sampling of Water Rehydration on Ligand Binding: A Comparison of Techniques.
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DOI：
10.1021/acs.jctc.1c00590
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发表时间：
2022-03-08
影响因子：
5.5
通讯作者：
Mobley, David L.
中科院分区：
文献类型：
--
作者：
Ge, Yunhui;Wych, David C.;Samways, Marley L.;Wall, Michael E.;Essex, Jonathan W.;Mobley, David L.
水通常在蛋白质结构、分子识别和介导蛋白质-配体相互作用中起关键作用。因此，自由能计算必须充分采样水的运动，这往往证明在典型的MD模拟时间尺度的挑战。因此，依赖于MD模拟的方法的准确性最终受到缓慢的水采样的限制。特别地，当配体被去除或修饰时，大量的水可能没有时间填充或重新排列在结合位点中。在这项工作中，我们专注于几个分子动力学（MD）模拟为基础的方法，试图帮助地下水再水合网站：蓝，使用非平衡候选人蒙特卡罗（NCMC）;盛大，使用巨正则蒙特卡罗（GCMC）;和正常MD。我们评估的准确性和效率，这些方法在再水化目标水网站。我们选择了一系列的系统与不同数量的沃茨的结合位点，以及那些水的占用耦合到身份或结合模式的配体。我们分析了再水化的结合口袋中使用的轨迹聚类和电子密度图的直接分析埋水网站。我们的研究结果表明，蓝和盛大提高水采样相对于正常的MD和盛大是更强大的比蓝，但水采样仍然是一个重大挑战，所有的测试方法。我们学到的这些方法和系统的经验教训进行了讨论。
Water often plays a key role in protein structure, molecular recognition, and mediating protein-ligand interactions. Thus, free energy calculations must adequately sample water motions, which often proves challenging in typical MD simulation timescales. Thus, the accuracy of methods relying on MD simulations ends up limited by slow water sampling. Particularly, as a ligand is removed or modified, bulk water may not have time to fill or rearrange in the binding site. In this work, we focus on several molecular dynamics (MD) simulation-based methods attempting to help rehydrate buried water sites: BLUES, using nonequilibrium candidate Monte Carlo (NCMC); grand, using grand canonical Monte Carlo (GCMC); and normal MD. We assess the accuracy and efficiency of these methods in rehydrating target water sites. We selected a range of systems with varying numbers of waters in the binding site, as well as those where water occupancy is coupled to the identity or binding mode of the ligand. We analyzed rehydration of buried water sites in binding pockets using both clustering of trajectories and direct analysis of electron density maps. Our results suggest both BLUES and grand enhance water sampling relative to normal MD and grand is more robust than BLUES, but also that water sampling remains a major challenge for all of the methods tested. The lessons we learned for these methods and systems are discussed.
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影响因子：
15
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
5.6
作者：
Bortolato, Andrea;Tehan, Ben G.;Mason, Jonathan S.
通讯作者：
Mason, Jonathan S.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.2
作者：
Bodnarchuk, Michael S.;Packer, Martin J.;Haywood, Alexe
通讯作者：
Haywood, Alexe
影响因子：
62.1
作者：
Bellissent-Funel MC;Hassanali A;Havenith M;Henchman R;Pohl P;Sterpone F;van der Spoel D;Xu Y;Garcia AE
通讯作者：
Garcia AE