期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 45, 页码 18413-18419出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja207470h
关键词
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资金
- NSF [MRI-R2-0960306, EF-0623664]
- NIH [R01-GM06-2868, NSF-DMS-0900700, NSF-MCB-0954714]
- NSF GRF
- Berry Foundation
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 mu s trajectories of the FiP35 WW domain (Shaw, D. E. et al. 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 mu s and 100 ns), within a factor of similar to 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.
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