title: Enthalpic Breakdown of Water Structure on Protein Active-Site Surfaces.
abstract: 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.
authors.affiliation: Department of Chemistry, Lehman College, The City University of New York , 250 Bedford Park Boulevard West, Bronx, New York 10468, United States.
authors.forename: Kamran
authors.initials: K
authors.lastname: Haider
authors.affiliation: Borough of Manhattan Community College, Department of Science, The City University of New York , 199 Chambers Street, New York, New York 10007, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Wickstrom
authors.affiliation: Department of Chemistry, Lehman College, The City University of New York , 250 Bedford Park Boulevard West, Bronx, New York 10468, United States.|Ph.D. Program in Biochemistry, The Graduate Center of The City University of New York , 365 Fifth Avenue, New York, New York 10016, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Ramsey
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093-0736, United States.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
authors.affiliation: Department of Chemistry, Lehman College, The City University of New York , 250 Bedford Park Boulevard West, Bronx, New York 10468, United States.|Ph.D. Program in Biochemistry, The Graduate Center of The City University of New York , 365 Fifth Avenue, New York, New York 10016, United States.|Ph.D. Program in Chemistry, The Graduate Center of The City University of New York , 365 Fifth Avenue, New York, New York 10016, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Kurtzman
mesh_terms: D020134:Catalytic Domain; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry*; D013499:Surface Properties; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D011506:Proteins; D014867:Water