title: Spatial Decomposition of Translational Water-Water Correlation Entropy in Binding Pockets.
abstract: A number of computational tools available today compute the thermodynamic properties of water at surfaces and in binding pockets by using inhomogeneous solvation theory (IST) to analyze explicit-solvent simulations. Such methods enable qualitative spatial mappings of both energy and entropy around a solute of interest and can also be applied quantitatively. However, the entropy estimates of existing methods have, to date, been almost entirely limited to the first-order terms in the IST's entropy expansion. These first-order terms account for localization and orientation of water molecules in the field of the solute but not for the modification of water-water correlations by the solute. Here, we present an extension of the Grid Inhomogeneous Solvation Theory (GIST) approach which accounts for water-water translational correlations. The method involves rewriting the two-point density of water in terms of a conditional density and utilizes the efficient nearest-neighbor entropy estimation approach. Spatial maps of this second order term, for water in and around the synthetic host cucurbit[7]uril and in the binding pocket of the enzyme Factor Xa, reveal mainly negative contributions, indicating solute-induced water-water correlations relative to bulk water; particularly strong signals are obtained for sites at the entrances of cavities or pockets. This second-order term thus enters with the same, negative, sign as the first order translational and orientational terms. Numerical and convergence properties of the methodology are examined.
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: Crystal N
authors.initials: CN
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, Lehman College, The City University of New York , 250 Bedford Park Blvd. West, Bronx, New York, New York 10468, United States.|Ph.D. Program in Chemistry, The Graduate Center of The City University of New York , New York 10016, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Kurtzman
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
mesh_terms: D001952:Bridged-Ring Compounds / Q000737:chemistry; D019277:Entropy; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry*; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D015951:Factor Xa; D007093:Imidazoles; D014867:Water; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils