Convergence and equilibrium in molecular dynamics simulations

Abstract

Abstract Molecular dynamics is a powerful tool that has been long used for the simulation of biomolecules. It complements experiments, by providing detailed information about individual atomic motions. But there is an essential and often overlooked assumption that, left unchecked, could invalidate any results from it: is the simulated trajectory long enough, so that the system has reached thermodynamic equilibrium, and the measured properties are converged? Previous studies showed mixed results in relation to this assumption. This has profound implications, as the resulting simulated trajectories may not be reliable in predicting equilibrium properties. Yet, this is precisely what most molecular dynamics studies do. So the question arises: are these studies even valid?Here, we present a thorough analysis of up to a hundred microseconds long trajectories, of several system with varying size, to probe the convergence of different structural, dynamical and cumulative properties, and elaborate on the relevance of the concept of equilibrium, and its physical and biological meaning. The results show that properties with the most biological interest tend to converge in multi-microsecond trajectories, although other properties–like transition rates to low probability conformations–may require more time.