Van der Waals Interactions Dominate Ligand-Protein Association in a Protein Binding Site Occluded from Solvent Water

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• 作者：Elizabeth Barratt ; Richard J. Bingham ; Daniel J. Warner ; Charles A. Laughton ; Simon E. V. Phillips ; and Steve W. Homans
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：August 24, 2005
• 年：2005
• 卷：127
• 期：33
• 页码：11827 - 11834
• 全文大小：358K
• 年卷期：v.127,no.33(August 24, 2005)
• ISSN：1520-5126

文摘

In the present study we examine the enthalpy of binding of 2-methoxy-3-isobutylpyrazine (IBMP)to the mouse major urinary protein (MUP), using a combination of isothermal titration calorimetry (ITC),NMR, X-ray crystallography, all-atom molecular dynamics simulations, and site-directed mutagenesis. Globalthermodynamics data derived from ITC indicate that binding is driven by favorable enthalpic contributions,rather than a classical entropy-driven signature that might be expected given that the binding pocket ofMUP-1 is very hydrophobic. The only ligand-protein hydrogen bond is formed between the side-chainhydroxyl of Tyr120 and the ring nitrogen of the ligand in the wild-type protein. ITC measurements on thebinding of IBMP to the Y120F mutant demonstrate a reduced enthalpy of binding, but nonetheless bindingis still enthalpy dominated. A combination of solvent isotopic substitution ITC measurements and all-atommolecular dynamics simulations with explicit inclusion of solvent water suggests that solvation is not amajor contributor to the overall binding enthalpy. Moreover, hydrogen/deuterium exchange measurementssuggest that there is no significant contribution to the enthalpy of binding derived from "tightening" of theprotein structure. Data are consistent with binding thermodynamics dominated by favorable dispersioninteractions, arising from the inequality of solvent-solute dispersion interactions before complexation versussolute-solute dispersion interactions after complexation, by virtue of poor solvation of the binding pocket.