APPLICATION OF RESP CHARGES TO CALCULATE CONFORMATIONAL ENERGIES, HYDROGEN-BOND ENERGIES, AND FREE-ENERGIES OF SOLVATION

We apply a new restrained electrostatic potential fit charge model (two-stage RESP) to conformational analysis and the calculation of intermolecular interactions. Specifically, we study conformational energies in butane, methyl ethyl thioether, three simple alcohols, three simple amines, and 1,2-ethanediol as a function of charge model (two-stage RESP vs standard ESP) and 1-4 electrostatic scale factor. We demonstrate that the two-stage RESP model with a 1-4 electrostatic scale factor of approximately 1/1.2 is a very good model, as evaluated by comparison with high-level ab initio calculations. For methanol and N-methylacetamide interactions with TIP3P water, the two-stage RESP model leads to hydrogen bonds only slightly weaker than found with the standard ESP changes. In tests on DNA base pairs, the two-stage RESP model leads to hydrogen bonds which are approximately 1 kcal/mol weaker than those calculated with the standard ESP charges but closer in magnitude to the best current available ab initio calculations. Furthermore, the two-stage RESP charges, unlike the standard ESP charges, reproduce the result that Hoogsteen hydrogen bonding is stronger than Watson-Crick hydrogen bonding for adenine-thymine base pairs. The free energies of solvation of both methanol and trans-N-methylacetamide were also calculated for the standard ESP and two-stage RESP models and both were in good agreement with experiment. We have combined the use of two-stage RESP charges with multiple conformational fitting-recently employed using standard ESP charges as described by Reynolds, et al. (J. Am. Chem. Soc. 1992, 114, 9075)-in studies of conformationally dependent dipole moments and energies of propylamine. We rind that the combination of these approaches is synergistic in leading to useful charge distributions for molecular simulations. Two-stage RESP charges thus reproduce both intermolecular and intramolecular energies and structures quite well, making this charge model a critical advancement in the development of a general force field for modeling biological macromolecules and their ligands, both in the gas phase and in solution.