Spatial Decomposition of Translational Water-Water Correlation Entropy in Binding Pockets

J Chem Theory Comput. 2016 Jan 12;12(1):414-29. doi: 10.1021/acs.jctc.5b00939. Epub 2015 Dec 4.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bridged-Ring Compounds / chemistry
  • Entropy
  • Factor Xa / chemistry
  • Factor Xa / metabolism
  • Imidazoles / chemistry
  • Models, Molecular
  • Protein Structure, Tertiary
  • Water / chemistry*

Substances

  • Bridged-Ring Compounds
  • Imidazoles
  • cucurbit(7)uril
  • Water
  • Factor Xa