Role of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand Binding

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• 作者：Robert Abel ; Tom Young ; Ramy Farid ; Bruce J. Berne ; Richard A. Friesner
• 刊名：Journal of the American Chemical Society
• 出版年：2008
• 出版时间：March 5, 2008
• 年：2008
• 卷：130
• 期：9
• 页码：2817 - 2831
• 全文大小：1164K
• 年卷期：v.130,no.9(March 5, 2008)
• ISSN：1520-5126

文摘

Understanding the underlying physics of the binding of small-molecule ligands to protein activesites is a key objective of computational chemistry and biology. It is widely believed that displacement ofwater molecules from the active site by the ligand is a principal (if not the dominant) source of binding freeenergy. Although continuum theories of hydration are routinely used to describe the contributions of thesolvent to the binding affinity of the complex, it is still an unsettled question as to whether or not thesecontinuum solvation theories describe the underlying molecular physics with sufficient accuracy to reliablyrank the binding affinities of a set of ligands for a given protein. Here we develop a novel, computationallyefficient descriptor of the contribution of the solvent to the binding free energy of a small molecule and itsassociated receptor that captures the effects of the ligand displacing the solvent from the protein activesite with atomic detail. This descriptor quantitatively predicts (R² = 0.81) the binding free energy differencesbetween 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 featuresof the hydration of the factor Xa active site relevant to the structure-activity relationship of its inhibitors.