All-Atom Folding and Characterization of the Free-Energy Landscape of the Villin Headpiece

The prediction of protein tertiary structure, in particular based on sequence information alone, remains one of the outstanding problems in biophysical chemistry. According to the thermodynamic hypothesis, the native conformation of a protein can be predicted as the global optimum of its free energy surface with stochastic optimization methods[1] orders of magnitude faster than by direct simulation of the folding process. We have recently developed an all-atom free energy forcefield[2]which implements a minimal thermodynamic model based on physical interactions . Using this forcefield we could reproducibly fold several proteins[3] ranging from 20-60 amino acids in length at the all atom level, among them the 36-amino acid, three helix villin headpiece. The conformations generated in the search can be used to construct a decoy tree, which completely characterizes the low energy conformations of the protein Consistent with the ``new paradigm'' for protein folding their analysis characterizes the folding funnel and its metastable branches. \newline [1] W. Wenzel, K. Hamacher, PRL 59, 3003 (1999) \newline [2] T. Herges, W. Wenzel, Biophysical J. 87, 3100 (2004) \newline [3] A. Schug, W. Wenzel, PRL 91, 158102 (2003), EPL 67, 307 (2004), Proteins (in press), PRL (in press), JACS (in press) \newline