Journal of Computer-Aided Molecular Design, 5 (1991) 5-20 ESCOM J-CAMD 100 The inclusion of electrostatic hydration energies in molecular mechanics calculations Michael K. Gilson and Barry Honig* Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, NY 10032, U.S.A. Received 5 June 1990 Accepted 30 June 1990 Key words: Force fields; Solvation energies SUMMARY The problem of including solvent effects in molecular mechanics calculations is discussed. It is argued that the neglect of charge-solvent (solvation) interactions can introduce significant errors. The finite difference Poisson-Boltzmann (FDPB) method for calculating electrostatic interactions is summarized and is used as a basis for introducing a new pairwise energy term which accounts for charge-solvent interactions. This term acts between all pairs of atoms usually considered in molecular mechanics calculations and can be easily in- corporated into existing force fields. As an example, a parameterization is developed for the CHARMm force field and the results compared to the predictions of the FDPB method. An approach to the realistic in- corporation of solvent screening into force fields is also outlined. INTRODUCTION Molecular mechanics calculations involve the use of a potential energy function which yields a molecule's energy as a function of conformation. The extent to which a calculation simulates physical reality thus depends critically on the accuracy of the energy function that is used. Stand- ard energy functions typically include terms for the stretching, bending, and twisting of chemical bonds, as well as terms which describe van der Waals and electrostatic interactions between non- bonded atoms. For molecules in solution, the calculations are complicated by the fact that solvent interactions can have profound effects on conformational energies. In the past few years, it has become common practice to account for solvent effects by including solvent molecules directly in the molecular mechanics force field. In this way, microscopic proper- ties of the solvent are accounted for explicitly. However, the calculations tend tO be computation- *To whom correspondence should be addressed. 0920-654X/$5.00 © 1991 ESCOM SciencePublishers B.V.