Nonbonded and torsional parameters for carboxylate esters, nitriles, and nitro compounds have been developed for the OPLS-AA force field. In addition, torsional parameters for alkanes have been updated. These parameters were fit to reproduce ab initio gas-phase structures and conformational energetics, experimental condensed-phase structural and thermodynamic properties, and experimental free energies of hydration. The computed densities, heats of vaporization, and heat capacities for fifteen liquids are in excellent agreement with experimental values. The new parameters permit accurate molecular modeling of compounds containing a wider variety of functional groups, which are common in organic molecules and drugs.

Monte Carlo/Extended Linear Response (MC/ELR) simulations have been conducted on 60 inhibitors of human factor Xa to determine the important interactions associated with their activity. A variety of physicochemical descriptors were configurationally averaged during the course of the simulations of each inhibitor bound to factor Xa and free in water. A regression equation was then derived; it reproduces the experimental inhibition data with a correlation coefficient, r(2), of 0.74, an rms error of 0.67 kcal/mol, and an average unsigned error of 0.60 kcal/mol using only two physically reasonable descriptors. The two factors that emerged as important in determining inhibitory potential are (1) favorable van der Waals interactions between protein and ligand and (2) direct hydrogen bonding between the inhibitor and protein. The conclusions were supported with structural analyses and results of MC/free energy perturbation (FEP) calculations.