Two-stage folding of HP-35 from ab initio simulations

Area of Science:

• Computational biology
• Biophysics
• Molecular dynamics simulations

Background:

• Accurate ab initio simulation of protein folding is essential for understanding protein structure and function.
• The villin headpiece subdomain (HP35) is a well-characterized small protein frequently used to test folding simulations.

Purpose of the Study:

• To demonstrate highly accurate folding of HP35 using all-atom molecular dynamics (MD) simulations.
• To elucidate the protein-folding mechanism and identify key residues involved in the process.

Main Methods:

• All-atom molecular dynamics simulations were performed using AMBER FF03 force field.
• Generalized-Born solvation model was employed to mimic aqueous environment.
• Multiple 20-microsecond simulations were conducted to capture folding trajectories.

Main Results:

• HP35 folded to its native state in multiple simulation trajectories, achieving a low C(alpha) RMSD of 0.39 Å for key residues.
• The native state was the most populated conformation, with the dominant cluster exhibiting a C(alpha) RMSD of 1.63 Å.
• Protein folding proceeded via a two-stage pathway, initiated by the formation of helices II and III.

Conclusions:

• All-atom MD simulations with the specified model can accurately predict protein folding.
• The folding pathway involves a distinct intermediate and a rate-limiting step involving specific residues (Phe17 and Pro21).
• This study provides detailed insights into folding kinetics and the roles of individual residues in HP35 folding.