Combined ab initio /empirical approach for optimization of Lennard‐Jones parameters for polar‐neutral compounds

The study of small functionalized organic molecules in aqueous solution is a useful step toward gaining a basic understanding of the behavior of biomolecular systems in their native aqueous environment. Interest in studying amines and fluorine‐substituted compounds has risen from their intrinsic physicochemical properties and their prevalence in biological and pharmaceutical compounds. In the present study, a previously developed approach which optimizes Lennard‐Jones (LJ) parameters via the use of rare gas atoms combined with the reproduction of experimental condensed phase properties was extended to polar–neutral compounds. Compounds studied included four amines (ammonia, methylamine, dimethylamine, and trimethylamine) and three fluoroethanes (1‐fluoroethane, 1,1‐difluoroethane, and 1,1,1‐trifluoroethane). The resulting force field yielded heats of vaporization and molecular volumes in excellent agreement with the experiment, with average differences less than 1%. The current amine CHARMM parameters successfully reproduced experimental aqueous solvation data where methylamine is more hydrophilic than ammonia, with hydrophobicity increasing with additional methylation on the nitrogen. For both the amines and fluoroethanes the parabolic relationship of the extent of methylation or fluorination, respectively, to the heats of vaporization were reproduced by the new parameters. The present results are also discussed with respect to the impact of parameterization approach to molecular details obtained from computer simulations and to the unique biological properties of fluorine in pharmaceutical compounds. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 199–213, 2002