title: Very empirical treatment of solvation and entropy: a force field derived from log Po/w.
abstract: A non-covalent interaction force field model derived from the partition coefficient of 1-octanol/water solubility is described. This model, HINT for Hydropathic INTeractions, is shown to include, in very empirical and approximate terms, all components of biomolecular associations, including hydrogen bonding, Coulombic interactions, hydrophobic interactions, entropy and solvation/desolvation. Particular emphasis is placed on: (1) demonstrating the relationship between the total empirical HINT score and free energy of association, deltaGinteraction; (2) showing that the HINT hydrophobic-polar interaction sub-score represents the energy cost of desolvation upon binding for interacting biomolecules; and (3) a new methodology for treating constrained water molecules as discrete independent small ligands. An example calculation is reported for dihydrofolate reductase (DHFR) bound with methotrexate (MTX). In that case the observed very tight binding, deltaGinteraction < or = -13.6 kcal mol(-1), is largely due to ten hydrogen bonds between the ligand and enzyme with estimated strength ranging between -0.4 and -2.3 kcal mol(-1). Four water molecules bridging between DHFR and MTX contribute an additional -1.7 kcal mol(-1) stability to the complex. The HINT estimate of the cost of desolvation is +13.9 kcal mol(-1).
authors.affiliation: Institute for Structural Biology and Drug Discovery & Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond 23298-0133 USA. Glen.Kellogg@vcu.edu
authors.forename: G E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: J C
authors.initials: JC
authors.lastname: Burnett
authors.forename: D J
authors.initials: DJ
authors.lastname: Abraham
mesh_terms: D020003:1-Octanol; D017076:Computer-Aided Design; D015195:Drug Design; D019277:Entropy; D004926:Escherichia coli / Q000201:enzymology; D006860:Hydrogen Bonding; D008024:Ligands; D008727:Methotrexate / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D012995:Solubility; D012997:Solvents; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014867:Water
chemical_list: D008024:Ligands; D012997:Solvents; D014867:Water; D013762:Tetrahydrofolate Dehydrogenase; D020003:1-Octanol; D008727:Methotrexate