title: Markov state model reveals folding and functional dynamics in ultra-long MD trajectories.
abstract: 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 μs 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 μs 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.
authors: Department of Chemistry, Stanford University, Stanford, California 94305, United States.
authors: Thomas J
authors: TJ
authors: Lane
authors: Gregory R
authors: GR
authors: Bowman
authors: Kyle
authors: K
authors: Beauchamp
authors: Vincent A
authors: VA
authors: Voelz
authors: Vijay S
authors: VS
authors: Pande
mesh_terms: D008390:Markov Chains; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins