Two-stage folding of HP-35 from ab initio simulations.
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 micros long simulations, the protein folded to the native state in multiple trajectories, with the lowest C(alpha) RMSD being 0.39 A 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 C(alpha) RMSD of 1.63 A. 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.
Lei
Hongxing
H
Genome Center and Department of Applied Science, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
Duan
Yong
Y
D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008840:Microfilament Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D008840:Microfilament Proteins; C026615:villin