The three-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH) molecular theory of solvation1-3 is Ornstein-Zernike type integral equation theory of liquids based on the first principles of statistical mechanics which consistently accounts for effect of chemical specificities of solvent, ions, and ligands on solvation structure and thermodynamics of biomolecules, including solvent exchange, structural solvent, desolvation, hydrophobicity, hydrogen bonding, salt bridges, and other effective interactions. The 3D-RISM-KH theory has been incorporated in drug design protocols. Using the 3D-RISM-KH theory for structural water detection4-7 and placement6,7 has been implemented in Amber Tools8 and in Molecular Operating Environment.9 It was shown that structural water plays critical role in the binding modes and the mechanisms of conformational change of Maltose-Binding Protein associated with Maltotriose ligand binding.10 With fragmental decomposition of flexible ligands treated as distinct species in solvent mixtures of arbitrary complexity, the computed density functions of solvent, ions, and ligand fragments are obtained from the 3D-RISM-KH theory as a set of discrete spatial grids that uniquely describe potentials of mean force around the protein solute.5,11,12 The latter define the scoring function interfaced with the AutoDock program for an automated ranking of docked conformations.12 As a case study, cooperative interactions encountered in the binding of a flexible thiamine molecule to the prion protein at near-physiological conditions were analyzed; the predicted location and residency times of computed binding modes are in excellent agreement with the available experimental data.12 (1) Molecular Theory of Solvation. Hirata, F. (ed.) Kluwer, Dordrecht, 2003. (2) J. Chem. Phys. 1999, 110, 10095. (3) Pure Appl. Chem. 2013, 85, 159. (4) J. Am. Chem. Soc. 2005, 127, 15334. (5) J. Phys. Chem. B 2009, 113, 873. (6) J. Comput. Chem. 2012, 33, 1536. (7) J. Phys. Chem. B 2013, 117, 6718. (8) Amber Tools 12 Reference Manual. http://Ambermd.Org/Doc12/Ambertools12.pdf (9) Chemical Computing Group. MOE™: Molecular Operating Environment. Structure-Based Design. http://www.chemcomp.com/MOE-Structure_Based_Design.htm (10) J. Chem. Inf. Model. 2015, 55, 317. (11) J. Am. Chem. Soc. 2009, 131, 12430. (12) J. Chem. Theory Comput. 2012, 8, 3356.

Structural solvent detection and placement and scoring functions for protein-ligand docking based on the 3D-RISM-KH molecular theory of solvation

251st National Meeting (2016)

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