Role of the active-site solvent in the thermodynamics of factor Xa ligand binding
Role of the active-site solvent in the thermodynamics of factor Xa ligand binding
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DOI：
10.1021/ja0771033
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发表时间：
2008-03-05
影响因子：
15
通讯作者：
Friesner, Richard A.
中科院分区：
文献类型：
--
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
了解小分子配体与蛋白质活性位点结合的基本物理过程是计算化学和生物学的一个关键目标。人们普遍认为，配体从活性位点置换水分子是结合自由能的主要（如果不是主导）来源。虽然连续理论的水化通常用于描述的贡献的溶剂的结合亲和力的复杂的，它仍然是一个悬而未决的问题，这些连续溶剂化理论是否描述了潜在的分子物理学与足够的准确性，可靠地排名的结合亲和力的一组配体的给定的蛋白质。在这里，我们开发了一种新的，计算效率高的描述符的贡献的溶剂的结合自由能的小分子和其相关的受体，捕获的配体取代溶剂从蛋白质活性位点与原子细节的影响。该描述符定量预测（R-2 = 0.81）测试系统因子Xa的同类配体对之间的结合自由能差异，阐明了在大多数连续理论中似乎缺少的活性位点溶剂的物理性质，并确定了因子Xa活性位点与其抑制剂的结构-活性关系相关的水合作用的几个特征。
Understanding the underlying physics of the binding of, small-molecule ligands to protein active sites is a key objective of computational chemistry and biology. It is widely believed that displacement of water molecules from the active site by the ligand is a principal (if not the dominant) source of binding free energy. Although continuum theories of hydration are routinely used to describe the contributions of the solvent to the binding affinity of the complex, it is still an unsettled question as to whether or not these continuum solvation theories describe the underlying molecular physics with sufficient accuracy to reliably rank the binding affinities of a set of ligands for a given protein. Here we develop a novel, computationally efficient descriptor of the contribution of the solvent to the binding free energy of a small molecule and its associated receptor that captures the effects of the ligand displacing the solvent from the protein active site with atomic detail. This descriptor quantitatively predicts (R-2 = 0.81) the binding free energy differences between congeneric ligand pairs for the test system factor Xa, elucidates physical properties of the active-site solvent that appear to be missing in most continuum theories of hydration, and identifies several features of the hydration of the factor Xa active site relevant to the structure-activity relationship of its inhibitors.