Interfaces and hydrophobic interactions in receptor-ligand systems: A level-set variational implicit solvent approach
Interfaces and hydrophobic interactions in receptor-ligand systems: A level-set variational implicit solvent approach
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DOI：
10.1063/1.3242274
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发表时间：
2009-10-14
影响因子：
4.4
通讯作者：
McCammon, J. Andrew
中科院分区：
文献类型：
--
作者：
Cheng, Li-Tien;Wang, Zhongming;McCammon, J. Andrew
采用水平集变分隐式溶剂模型（VISM）研究了水溶液中的纳米疏水受体-配体体系。这种方法是比较全原子计算机模拟。模拟揭示复杂的水合作用（凹）受体口袋内，敏感的（凸）接近配体的距离。配体诱导并控制宿主口袋的干态和湿态之间的间歇性切换，这决定了口袋-配体吸引力的范围和大小。在水平集VISM中，所有可能的溶质-溶剂界面与局部分散势耦合的几何自由能泛函在数值上被最小化。这种方法捕捉到不同的亚稳态，对应于拓扑结构不同的溶质-溶剂界面，从而再现了双峰水合行为中观察到的全原子模拟。在界面弛豫过程中形成的几何奇异性被发现显着地有助于不同的亚稳态之间的能量势垒。虽然水化现象，因此可以解释的毛细管效应，明确列入的分散和曲率修正似乎是必不可少的定量描述的疏水限制系统的纳米尺度。这项研究可能会揭示更多的生物分子水合作用的几何和能量方面之间的紧密联系，并可能代表一个有价值的一步，对实验受体配体结合率的正确解释。(C)2009年美国物理学会。[doi：10.1063/1.3242274]
A model nanometer-sized hydrophobic receptor-ligand system in aqueous solution is studied by the recently developed level-set variational implicit solvent model (VISM). This approach is compared to all-atom computer simulations. The simulations reveal complex hydration effects within the (concave) receptor pocket, sensitive to the distance of the (convex) approaching ligand. The ligand induces and controls an intermittent switching between dry and wet states of the hosting pocket, which determines the range and magnitude of the pocket-ligand attraction. In the level-set VISM, a geometric free-energy functional of all possible solute-solvent interfaces coupled to the local dispersion potential is minimized numerically. This approach captures the distinct metastable states that correspond to topologically different solute-solvent interfaces, and thereby reproduces the bimodal hydration behavior observed in the all-atom simulation. Geometrical singularities formed during the interface relaxation are found to contribute significantly to the energy barrier between different metastable states. While the hydration phenomena can thus be explained by capillary effects, the explicit inclusion of dispersion and curvature corrections seems to be essential for a quantitative description of hydrophobically confined systems on nanoscales. This study may shed more light onto the tight connection between geometric and energetic aspects of biomolecular hydration and may represent a valuable step toward the proper interpretation of experimental receptor-ligand binding rates. (C) 2009 American Institute of Physics. [doi:10.1063/1.3242274]