Haider Kamran, Wickstrom Lauren, Ramsey Steven, Gilson Michael K, Kurtzman Tom
Department of Chemistry, Lehman College, The City University of New York , 250 Bedford Park Boulevard West, Bronx, New York 10468, United States.
Borough of Manhattan Community College, Department of Science, The City University of New York , 199 Chambers Street, New York, New York 10007, United States.
J Phys Chem B. 2016 Sep 1;120(34):8743-56. doi: 10.1021/acs.jpcb.6b01094. Epub 2016 Jun 2.
The principles underlying water reorganization around simple nonpolar solutes are well understood and provide the framework for the classical hydrophobic effect, whereby water molecules structure themselves around solutes so that they maintain favorable energetic contacts with both the solute and the other water molecules. However, for certain solute surface topographies, water molecules, due to their geometry and size, are unable to simultaneously maintain favorable energetic contacts with both the surface and neighboring water molecules. In this study, we analyze the solvation of ligand-binding sites for six structurally diverse proteins using hydration site analysis and measures of local water structure, in order to identify surfaces at which water molecules are unable to structure themselves in a way that maintains favorable enthalpy relative to bulk water. These surfaces are characterized by a high degree of enclosure, weak solute-water interactions, and surface constraints that induce unfavorable pair interactions between neighboring water molecules. Additionally, we find that the solvation of charged side chains in an active site generally results in favorable enthalpy but can also lead to pair interactions between neighboring water molecules that are significantly unfavorable relative to bulk water. We find that frustrated local structure can occur not only in apolar and weakly polar pockets, where overall enthalpy tends to be unfavorable, but also in charged pockets, where overall water enthalpy tends to be favorable. The characterization of local water structure in these terms may prove useful for evaluating the displacement of water from diverse protein active-site environments.
简单非极性溶质周围水重组的基本原理已得到充分理解，并为经典疏水效应提供了框架，即水分子围绕溶质形成结构，以便它们与溶质和其他水分子都保持有利的能量接触。然而，对于某些溶质表面形貌，由于水分子的几何形状和大小，它们无法同时与表面和相邻水分子保持有利的能量接触。在本研究中，我们使用水合位点分析和局部水结构测量方法，分析了六种结构不同蛋白质的配体结合位点的溶剂化情况，以确定水分子无法以相对于本体水保持有利焓的方式形成自身结构的表面。这些表面的特征是高度封闭、溶质 - 水相互作用较弱以及表面限制会导致相邻水分子之间产生不利的成对相互作用。此外，我们发现活性位点中带电侧链的溶剂化通常会导致有利的焓，但也可能导致相邻水分子之间的成对相互作用相对于本体水明显不利。我们发现，不仅在整体焓往往不利的非极性和弱极性口袋中会出现受阻的局部结构，在整体水焓往往有利的带电口袋中也会出现。用这些术语表征局部水结构可能有助于评估不同蛋白质活性位点环境中水的置换情况。
