MC(JBW) - SIMPLE BUT SMART MONTE-CARLO ALGORITHM FOR FREE-ENERGY SIMULATIONS OF MULTICONFORMATIONAL MOLECULES

Many of the most common molecular simulation methods, including Monte Carlo (MC) and molecular or stochastic dynamics (MD or SD), have signi ficant difficulties in sampling the space of molecular potential energ y surfaces characterized by multiple conformational minima and signifi cant energy barriers. In such cases improved sampling can be obtained by special techniques that lower such barriers or somehow direct searc h steps toward different low energy regions of space. We recently desc ribed a hybrid MC/SD algorithm [MC(JBW)/SD] incorporating such a techn ique that directed MC moves of selected torsion and bond angles toward known low energy regions of conformational space. Exploration of othe r degrees of freedom was left to the SD part of the hybrid algorithm. In the work described here, we develop a related but simpler simulatio n algorithm that uses only MC to sample all degrees of freedom (e.g., stretch, bend, and torsion). We term this algorithm MC(JBW). Using sim ulations on various model potential energy surfaces and on simple mole cular systems (n-pentane, n-butane, and cyclohexane), MC(JBW) is shown to generate ensembles of states that are indistinguishable from the c anonical ensembles generated by classical Metropolis MC in the limit o f very long simulations. We further demonstrate the utility of MC(JBW) by evaluating the room temperature free energy differences between co nformers of various substituted cyclohexanes and the larger ring hydro carbons cycloheptane, cyclooctane, cyclononane, and cyclodecane. The r esults compare favorably with available experimental data and results from previously reported MC(JBW)/SD conformational free energy calcula tions. (C) 1998 John Wiley & Sons, Inc.