Comparison of the molecular mechanics + generalized Born/surface area and the ab initio + Monte Carlo simulation methods in estimating conformational equilibria in aqueous solution

Abstract

AbstractA method using molecular mechanics to calculate internal energies and the generalized Born/surface area (GB/SA) method for calculating solvation free energy has been compared with the corresponding terms obtained from ab initio quantum chemical calculations in the gas phase and the free energy perturbation method implemented in Monte Carlo (MC) simulations to study conformational equilibria in solution. 1,2‐Ethanediol, 2‐hydroxybenzoic acid, the neutral and protonated histamine, were considered in aqueous solution as systems capable of intramolecular hydrogen bonding. The molecular mechanics method with all atom and united atom models, using the AMBER* force field and the parameterization as implemented in the MacroModel modeling package and the GB/SA continuum solvation model, produces smaller separation in relative conformer free energies than does the ab initio + MC method in aqueous solution. The GB/SA relative solvation free energies using the charges from the AMBER* force fields were consistently smaller than the values obtained in Monte Carlo simulations. Using the charge sets from the Monte Carlo simulations and considering solute geometries with torsional angles fixed at the optimized ab initio values, the relative solvation free energies remained underestimated by up to 30% as compared to the Monte Carlo values. The AMBER*//GB/SA predicted most stable conformer for the 1,2‐ethandiol system in aqueous solution is in contrast with the ab initio + MC finding and the available experimental results. For the histamine system predictions by only the united atom AMBER*//GB/SA model agree with those by ab initio + MC and with data derived from nuclear magnetic resonance (NMR) experiments. Differences in the two methods are considered mainly due to the application of torsional parameters and atomic charges developed in the AMBER* parameter set for monofunctional polar systems. New parameters seem to be needed for quantitative description of the in‐solution conformational equilibria for organic compounds with a possible intramolecular hydrogen bond. © 1994 by John Wiley & Sons, Inc.