A historical perspective on the application of molecular dynamics (MD) to biological macromolecules is presented. Recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed us to reach the fourth era of MD applications in which one can often derive both accurate structure and accurate relative free energies from molecular dynamics trajectories. We illustrate such applications on nucleic acid duplexes, RNA hairpins, protein folding trajectories, and proteinligand, protein-protein, and protein-nucleic acid interactions.

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The weighted ensemble (WE) methodology orchestrates quasi-independent parallel simulations run with intermittent communication that can enhance sampling of rare events such as protein conformational changes, folding, and binding. The WE strategy can achieve superlinear scaling—the unbiased estimation of key observables such as rate constants and equilibrium state populations to greater precision than would be possible with ordinary parallel simulation. WE software can be used to control any dynamics engine, such as standard molecular dynamics and cell-modeling packages. This article reviews the theoretical basis of WE and goes on to describe successful applications to a number of complex biological processes—protein conformational transitions, (un)binding, and assembly processes, as well as cell-scale processes in systems biology. We furthermore discuss the challenges that need to be overcome in the next phase of WE methodological development. Overall, the combined advances in WE methodology and software have enabled the simulation of long-timescale processes that would otherwise not be practical on typical computing resources using standard simulation.