分子模拟中从分子群体到绝对结合亲和力：精确体积项与实用估计器
From populations to absolute binding affinities in molecular simulations: exact volumetric terms and practical estimators
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中文总结 AI 辅助
本研究提出统计力学框架，推导结合常数K与分子群体的关联式，应用于两种复合物发现常用估计器有偏差，为从分子模拟获取绝对结合亲和力提供原则性途径。
中文摘要 AI 辅助
我们提出了一种用于计算稀溶液极限下平衡结合常数K的统计力学框架。从第一性原理出发，我们推导了将K与结合态和未结合态的相对群体关联起来的通用表达式。该表达式的透明性具有双重优势：它明确了未结合态体积项的来源，且能精确追踪施加的体积限制如何在表达式中传播。在未结合态为均匀的物理上温和假设下，受限模拟可精确考虑体积贡献，这使得K可直接计算。所得估计器可从任何适当定义的反应坐标的直方图中计算，并明确确定需如何定义目标热力学状态的边界。我们将该框架应用于葫芦[7]脲/1-金刚烷胺主客体复合物以及半乳糖酸-DgoT配体-蛋白质复合物。结果显示，常用的单箱估计器在两种体系中与理论正确值的偏差约为1 kcal/mol。该偏差源于结合态的定义：通过将该定义锚定到最先进实验所解析的内容，理论将其从隐藏假设转变为可控输入，为从分子模拟中获取绝对结合亲和力提供了有原则的途径。
英文摘要
We present a statistical-mechanics framework for computing equilibrium binding constants $K$ in the dilute limit. From first principles, we derive a general expression relating $K$ to the relative populations of the bound and unbound states. Its transparency has twofold advantage: it makes the origin of the unbound-state volumetric term explicit, and it allows one to track exactly how an imposed volume restraint propagates through the expression. This makes $K$ directly computable, as restrained simulations can account for the volumetric contribution exactly, under the physically mild assumption of a homogeneous unbound state. The resulting estimators are computable from histograms of any suitably defined reaction coordinate, and determine unambiguously how the boundaries of the thermodynamic states of interest must be defined. We apply our framework to the cucurbit[7]uril/1-adamantanol host--guest complex and the galactonate--DgoT ligand--protein complex. Our results show that commonly used single-bin estimators depart from the theoretically correct one by $\approx 1$~kcal/mol in both systems. This shift originates in the definition of the bound state: by anchoring that definition to what state-of-the-art experiments resolve, the theory turns it from a hidden assumption into a controlled input, and provides a principled route to absolute binding affinities from molecular simulations.
