Transition Path Time Distribution Research Articles

Transition Path Times in Protein Folding Studied by Structure-Based Simulation

In trajectories of protein folding and unfolding processes, the transition path that connects denatured and native states is the most interesting part. Recently, single-molecule FRET experiments together with a statistical inference theory successfully identified the transition path times for folding of some small proteins. Yet, its underlying physics is poorly understood. Here we conducted a comprehensive survey of transition path times for 29 small-to-medium two-state-folding proteins using structure-based coarse-grained molecular dynamics simulations. Using the multi-canonical ensemble method, we first identified folding transition temperature accurately. At the transition temperature, we then performed relatively long simulations observing reversible folding and unfolding events, from which we identified and analyzed the transition path times. The distribution of transition path time for each protein can be explained as free diffusion of particle in a reaction coordinate. We sought what reaction coordinates correlate with the transition path time. Among tested coordinates, we found that the average transition path time is most strongly correlated to the difference in the numbers of native contacts, i.e., contact energies, between native and denatured states. These results imply that the transition path time series can be approximated as the nearly free diffusion in the reaction coordinate of native contacts.