Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2188429 | Journal of Molecular Biology | 2007 | 11 Pages |
Accurate ab initio simulation of protein folding is a critical step toward elucidation of protein-folding mechanisms. Here, we demonstrate highly accurate folding of the 35 residue villin headpiece subdomain (HP35) by all-atom molecular dynamics simulations using AMBER FF03 and the generalized-Born solvation model. In a set of 20 μs long simulations, the protein folded to the native state in multiple trajectories, with the lowest Cα RMSD being 0.39 Å for residues 2–34 (excluding residues 1 and 35). The native state had the highest population among all sampled conformations, and the center of most populated cluster had a Cα RMSD of 1.63 Å. Folding of this protein can be described as a two-stage process that followed a well-defined pathway. In the first stage, formation of helices II and III as a folding intermediate constituted the rate-limiting step and was initiated at a folding nucleus around residues Phe17 and Pro21. The folding intermediate further acted as a template that facilitated the folding and docking of helix I in the second stage. Detailed descriptions of the folding kinetics and the roles of key residues are presented.