Very empirical treatment of solvation and entropy: a force field derived from Log P-o/w

A non-covalent interaction force field model derived from the partition coe fficient of 1-octanol/water solubility is described. This model, HINT for H ydropathic INTeractions, is shown to include, in very empirical and approxi mate terms, all components of biomolecular associations, including hydrogen bonding, Coulombic interactions, hydrophobic interactions, entropy and sol vation/desolvation. Particular emphasis is placed on: (1) demonstrating the relationship between the total empirical HINT score and free energy of ass ociation, DeltaG(interaction); (2) showing that the HINT hydrophobic-polar interaction sub-score represents the energy cost of desolvation upon bindin g for interacting biomolecules; and (3) a new methodology for treating cons trained water molecules as discrete independent small ligands. An example c alculation is reported for dihydrofolate reductase (DHFR) bound with methot rexate (MTX). In that case the observed very tight binding, DeltaG(interact ion)less than or equal to -13.6 kcal mol(-1), is largely due to ten hydroge n bonds between the ligand and enzyme with estimated strength ranging betwe en -0.4 and -2.3 kcal mol(-)1. Four water molecules bridging between DHFR a nd 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).