Convergence of replica exchange molecular dynamics.

Replica exchange molecular dynamics (REMD) method is one of the generalized-ensemble algorithms which performs random walk in energy space and helps a system to escape from local energy traps. In this work, we studied the accuracy and efficiency of REMD by examining its ability to reproduce the results of multiple extended conventional molecular dynamics (MD) simulations and to enhance conformational sampling. Two sets of REMD simulations with different initial configurations, one from the fully extended and the other from fully helical conformations, were conducted on a fast-folding 21-amino-acid peptide with a continuum solvent model. Remarkably, the two REMD simulation sets started to converge even within 1.0 ns, despite their dramatically different starting conformations. In contrast, the conventional MD within the same time and with identical starting conformations did not show obvious signs of convergence. Excellent convergence between the REMD sets for T>300 K was observed after 14.0 ns REMD simulations as measured by the average helicity and free-energy profiles. We also conducted a set of 45 MD simulations at nine different temperatures with each trajectory simulated to 100.0 and 200.0 ns. An excellent agreement between the REMD and the extended MD simulation results was observed for T>300 K, showing that REMD can accurately reproduce long-time MD results with high efficiency. The autocorrelation times of the calculated helicity demonstrate that REMD can significantly enhance the sampling efficiency by 14.3+/-6.4, 35.1+/-0.2, and 71.5+/-20.4 times at, respectively, approximately 360, approximately 300, and approximately 275 K in comparison to the regular MD. Convergence was less satisfactory at low temperatures (T<300 K) and a slow oscillatory behavior suggests that longer simulation time was needed to reach equilibrium. Other technical issues, including choice of exchange frequency, were also examined.