LAUSR

By using an approach that allows computing the free energy in high-dimensional spaces together with a clustering technique capable of identifying kinetic attractors stabilized by entropy, we analyze a molecular dynamics trajectory of the Villin headpiece from Ref.1. We compute its free energy landscape in the space of all its Cα carbons. This landscape has the shape of a twelve-dimensional funnel. The global free energy minimum corresponds to the folded state and there are no significant folding barriers. The funnel can be partitioned in five regions, three mainly folded and two unfolded, which behave as Markov States. The slowest relaxation time among these states corresponds to the folding transition. The second slowest time is only twice smaller and corresponds to a transition within the unfolded state. This indicates that the unfolded part of the funnel has a non-trivial shape, which induces a sizable kinetic barrier between disordered states.