Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo.
Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo.
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DOI：
10.1021/acs.jctc.2c00823
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发表时间：
2023-02-14
影响因子：
5.5
通讯作者：
Essex, Jonathan W.
中科院分区：
文献类型：
--
作者：
Melling, Oliver J.;Samways, Marley L.;Ge, Yunhui;Mobley, David L.;Essex, Jonathan W.
水分子在许多生物分子系统中起着关键作用，特别是当结合在蛋白质-配体界面时。然而，蛋白质和溶剂之间发生水交换的时间尺度相对较长，阻碍了对此类系统的分子模拟研究。巨正则蒙特卡罗（GCMC）是一种模拟技术，通过尝试在给定结构中插入和删除水分子来避免这个问题。然而，该方法受到拥塞系统中插入的低接受概率的限制。为了解决这个问题，在这里，我们结合联合收割机GCMC与非平衡候选蒙特卡罗（NCMC）产生的方法，我们称之为巨正则非平衡候选蒙特卡罗（GCNCMC），其中的水插入和删除进行了一个渐进的，非平衡的方式。我们通过比较GCNCMC和GCMC模拟散装水和三个蛋白质结合位点来验证这种新方法。我们发现，不仅是水采样的效率提高了GCNCMC，但它也导致在蛋白质结合位点的配体构象的采样增加，揭示了新的水介导的配体结合的几何形状，没有观察到使用替代增强的采样技术。
Water molecules play a key role in many biomolecular systems, particularly when bound at protein–ligand interfaces. However, molecular simulation studies on such systems are hampered by the relatively long time scales over which water exchange between a protein and solvent takes place. Grand canonical Monte Carlo (GCMC) is a simulation technique that avoids this issue by attempting the insertion and deletion of water molecules within a given structure. The approach is constrained by low acceptance probabilities for insertions in congested systems, however. To address this issue, here, we combine GCMC with nonequilibium candidate Monte Carlo (NCMC) to yield a method that we refer to as grand canonical nonequilibrium candidate Monte Carlo (GCNCMC), in which the water insertions and deletions are carried out in a gradual, nonequilibrium fashion. We validate this new approach by comparing GCNCMC and GCMC simulations of bulk water and three protein binding sites. We find that not only is the efficiency of the water sampling improved by GCNCMC but that it also results in increased sampling of ligand conformations in a protein binding site, revealing new water-mediated ligand-binding geometries that are not observed using alternative enhanced sampling techniques.
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