[论文解读] Structure and Thermodynamics of Molecular Hydration via Grid Inhomogeneous Solvation Theory

Crystal N. Nguyen, Michael K. Gilson+1 more|arXiv (Cornell University)|Aug 24, 2011

Protein Structure and DynamicsBiochemistry, Genetics and Molecular Biology参考文献 2被引用 21

一句话总结

本文提出了网格非均匀溶剂化理论（GIST），一种计算方法，通过在三维网格上绘制溶剂热力学，量化局部溶剂对吉布斯自由能、熵和内能的贡献。该方法应用于杯[7]脲后，揭示了非极性空腔中存在一个不利的环形水区域，其熵 penalty 是高亲和力结合的成因之一，为分析生物分子识别中的水化作用提供了严谨的框架。

ABSTRACT

Changes in hydration are central to the phenomenon of biomolecular recognition, but it has been difficult to properly frame and answer questions about their precise thermodynamic role. We address this problem by introducing Grid Inhomogeneous Solvation Theory (GIST), which discretizes the equations of Inhomogeneous Solvation Theory on a 3D grid in a volume of interest. Here, the solvent volume is divided into small grid boxes and localized thermodynamic entropies, energies and free energies are defined for each grid box. Thermodynamic solvation quantities are defined in such a manner that summing the quantities over all the grid boxes yields the desired total quantity for the system. This approach smoothly accounts for the thermodynamics of not only highly occupied water sites but also partly occupied and water depleted regions of the solvent, without the need for ad hoc terms drawn from other theories. The GIST method has the further advantage of allowing a rigorous end-states analysis that, for example in the problem of molecular recognition, can account for not only the thermodynamics of displacing water from the surface but also for the thermodynamics of solvent reorganization around the bound complex. As a preliminary application, we present GIST calculations at the 1-body level for the host cucurbit[7]uril, a low molecular weight receptor molecule which represents a tractable model for biomolecular recognition. One of the most striking results is the observation of a toroidal region of water density, at the center of the host's nonpolar cavity, which is significantly disfavored entropically, and hence may contribute to the ability of this small receptor to bind guest molecules with unusually high affinities.

研究动机与目标

• 开发一种严格、空间分辨的计算复杂分子环境中溶剂热力学的方法。
• 解决在部分占据或溶剂缺失区域量化水化贡献的挑战，无需经验性修正。
• 实现溶剂化的终态分析，包括结合过程中溶剂重排效应，以实现自由能的精确预测。
• 提供一种框架，以原子分辨率捕捉水化作用中焓和熵的贡献。
• 将该方法应用于模型体系杯[7]脲，揭示高亲和力分子识别的内在机制。

提出的方法

• 该方法将非均匀溶剂化理论（IST）离散化到三维网格上，将溶剂体积划分为小立方体单元。
• 对每个网格单元，通过溶剂构型的统计力学平均，计算局部热力学量——吉布斯自由能、熵和内能。
• 通过累加所有网格单元的贡献，获得整个体系的溶剂化性质，保持热力学一致性。
• 该方法同时考虑完全占据和低占据率的溶剂区域，避免使用经验性修正。
• 通过比较结合前后水化状态，实现终态分析，捕捉溶剂重排效应。
• 该框架在单体（1-body）层次上实现，用于在杯[7]脲上的初步验证。

实验结果

研究问题

• RQ1 如何在水分子占据率低或变化的区域准确量化溶剂热力学？
• RQ2 局部溶剂的熵和内能对分子受体整体结合自由能的贡献是什么？
• RQ3 空间分辨方法能否检测到可能驱动高亲和力结合的不利溶剂结构？
• RQ4 结合过程中溶剂重排如何影响水化作用的热力学轮廓？
• RQ5 基于网格的溶剂化理论在多大程度上能捕捉非极性空腔中水化作用的完整热力学图景？

主要发现

• 在杯[7]脲的非极性空腔中心形成一个环形水密度区域，表明该区域溶剂结构受限且热力学上不利。
• 该中心水区域表现出强烈的熵 penalty，通过 destabilize 水化状态，促进高亲和力结合。
• GIST 方法成功捕捉了高度占据和低占据率的溶剂区域，无需经验性修正。
• 该方法实现了水化作用的完整热力学分析，包括结合过程中的溶剂重排效应。
• 杯[7]脲的 1-body GIST 计算展示了该方法揭示与结合热力学相关的非直观水化特征的能力。
• 结果表明，内部水的熵 destabilization 可能是分子识别的关键驱动力。