Markov state model reveals folding and functional dynamics in ultra-long MD trajectories

Two strategies have been recently employed to push molecular simulation to long, biologically relevant time scales: projection-based analysis of results from specialized hardware producing a small number of ultralong trajectories and the statistical interpretation of massive parallel sampling performed with Markov state models (MSMs). Here, we assess the MSM as an analysis method by constructing a Markov model from ultralong trajectories, specifically two previously reported 100 micros trajectories of the FiP35 WW domain (Shaw, D. E. Science 2010, 330, 341-346). We find that the MSM approach yields novel insights. It discovers new statistically significant folding pathways, in which either beta-hairpin of the WW domain can form first. The rates of this process approach experimental values in a direct quantitative comparison (time scales of 5.0 micros and 100 ns), within a factor of ∼2. Finally, the hub-like topology of the MSM and identification of a holo conformation predicts how WW domains may function through a conformational selection mechanism.