Protein Structure Prediction with Stochastic Optimization Methods: Folding and Misfolding the Villin Headpiece

We recently developed an all-atom free energy forcefield (PFF01) for protein structure prediction with stochastic optimization methods. Using this forcefield we were able to reproducibly fold the 20 amino-acid trp-cage protein and the 40-amino acid three-helix HIV accessory protein. We could also demonstrate that PFF01 stabilized the native folds of various other proteins ranging from 40-60 amino acids at the all atom level. Here we report on a folding study on the widely investigated autonomously folding 36-amino acid villin headpiece. Using more than 76000 low-energy decoys to characterize its free-energy landscape, we find several competing low-lying three-helix structures. The existence of these metastable conformations, which are not nearly as prevalent in other proteins, may explain the extreme difficulty in folding this protein in-silico.

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