FREE-ENERGIES OF HYDRATION FROM THERMODYNAMIC INTEGRATION - COMPARISON OF MOLECULAR MECHANICS FORCE-FIELDS AND EVALUATION OF CALCULATION ACCURACY

Four commonly used molecular mechanics force fields, CHARMM22, OPLS, C VFF, and GROMOS87, are compared for their ability to reproduce experim ental free energies of hydration (Delta G(hydr)) from molecular dynami cs (MD) simulations for a set of small nonpolar and polar organic mole cules: propane, cyclopropane, dimethylether, and acetone. Delta G(hydr ) values were calculated by multiconfiguration thermodynamic integrati on for each of the different force fields with three different sets of partial atomic charges: full charges from an electrostatic potential fit (ESP), and ESP charges scaled by 0.8 and 0.6. All force fields, ex cept for GROMOS87, give reasonable results for Delta G(hydr) if partia l atomic charges of appropriate magnitude are assigned. For GROMOS87, the agreement with experiment for hydrocarbons (propane and ethane) wa s improved considerably by modifying the repulsive part of the carbon- water oxygen Lennard-Jones potential. The small molecules studied are related to the chemical moieties constituting camphor (C10H16O). By in voking force-field transferability, we calculated the Delta G(hydr) fo r camphor. With the modified GROMOS force field, a Delta G(hydr) withi n 4 kJ/mol of the experimental value of - 14.8 kJ/mol was obtained. Ca mphor is one of the largest molecules for which an absolute hydration free energy has been calculated by molecular simulation. The accuracy and reliability of the thermodynamic integration calculations were ana lyzed in detail and we found that, for Delta G(hydr) calculations for the set of small molecules in aqueous solution, molecular dynamics sim ulations of 0.8-1.0 ns in length give an upper statistical error bound of 1.5 kJ/mol, whereas shorter simulations of 0.25 nm in length given an upper statistical error bound of 3.5 kJ/mol. (C) 1997 by John Wile y & Sons, Inc.