All-atom Metadynamics Simulations of the Hierarchical Folding Dynamics of Proteins on the Timescale of Seconds

Molecular dynamics simulations have proven instrumental to the understanding of molecular biophysics. However, the temporal constraints of molecular dynamics simulations have limited attempts to capture the protein folding process at the atomic scale. Herein, we circumvent this limitation by using all-atom metadynamics algorithm to directly sample the potential-energy landscape of numerous proteins. Previous applications of the original metadynamics method to proteins penalized select collective variables of the protein assumed to be principle to the folding process. Rather, our method penalizes the full coordinate space of the protein resulting in a 3N-dimensional sampled energy-landscape, unbiased by a priori assumptions. With all-atom sampling, over collective variable sampling, a single simulation captures the folding and unfolding process multiple times, enabling the simulation of protein dynamics on scales of seconds, orders of magnitude longer than recorded molecular dynamics simulations. Further, we predict the folded state of the protein, and the activation barrier and the timescale associated with the folding process of the proteins. We will present these findings for several well-studied proteins, to validate our results, and several new proteins, as a novel extension.