A rapidly convergent simulation method: Mixed Monte Carlo/stochastic dynamics

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Abstract
Although Monte Carlo and molecular dynamics are the primary methods used for free energy simulations of molecular systems, their application to molecules that have multiple conformations separated by energy barriers of ≥ 3 kcal/mol is problematic because of slow rates of convergence. In this article we introduce a hybrid simulation method termed MC‐SD which mixes Monte Carlo (MC) and stochastic dynamics (SD). This new method generates a canonical ensemble via alternating MC and SD steps and combines the local exploration strengths of dynamics with the barrier‐crossing ability of large‐step Monte Carlo. Using calculations on double‐well potentials and long simulations (108 steps of MC and 1 μs of SD) of the simple, conformationally flexible molecule n‐pentane, we find that MC‐SD simulations converage faster than either MC or SD alone and generate ensembles which are equivalent to those created by classical MC or SD. Using pure SD at 300 K, the conformational populations of n‐pentane are shown to be poorly converged even after a full microsecond of simulation. © 1994 by John Wiley & Sons, Inc.