Protein folding is a complex multidimensional process that is difficult to illustrate by the traditional analyses based on one- or two-dimensional profiles. Analyses based on transition networks have become an alternative approach that has the potential to reveal detailed features of protein folding dynamics. However, due to the lack of successful reversible folding of proteins from conventional molecular-dynamics simulations, this approach has rarely been utilized. Here, we analyzed the folding network from several 10 μs conventional molecular-dynamics reversible folding trajectories of villin headpiece subdomain (HP35). The folding network revealed more complexity than the traditional two-dimensional map and demonstrated a variety of conformations in the unfolded state, intermediate states, and the native state. Of note, deep enthalpic traps at the unfolded state were observed on the folding landscape. Furthermore, in contrast to the clear separation of the native state and the primary intermediate state shown on the two-dimensional map, the two states were mingled on the folding network, and prevalent interstate transitions were observed between these two states. A more complete picture of the folding mechanism ofHP35 emerged when the traditional and network analyses were considered together. © 2010 by the Biophysical Society.
Lei, H., Su, Y., Jin, L., & Duan, Y. (2010). Folding network of villin headpiece subdomain. Biophysical Journal, 99(10), 3374–3384. https://doi.org/10.1016/j.bpj.2010.08.081