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Molecular Simulation of ab Initio Protein Folding for a Millisecond Folder NTL9(1−39)

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Departments of Chemistry and Structural Biology, Stanford University, Stanford, California 94305, and Biophysics Program, Stanford University, Stanford, California 94305
[email protected]
†Department of Chemistry.
‡Department of Structural Biology.
§Biophysics Program.
Cite this: J. Am. Chem. Soc. 2010, 132, 5, 1526–1528
Publication Date (Web):January 13, 2010
https://doi.org/10.1021/ja9090353
Copyright © 2010 American Chemical Society
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    Abstract

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    To date, the slowest-folding proteins folded ab initio by all-atom molecular dynamics simulations have had folding times in the range of nanoseconds to microseconds. We report simulations of several folding trajectories of NTL9(1−39), a protein which has a folding time of ∼1.5 ms. Distributed molecular dynamics simulations in implicit solvent on GPU processors were used to generate ensembles of trajectories out to ∼40 μs for several temperatures and starting states. At a temperature less than the melting point of the force field, we observe a small number of productive folding events, consistent with predictions from a model of parallel uncoupled two-state simulations. The posterior distribution of the folding rate predicted from the data agrees well with the experimental folding rate (∼640/s). Markov State Models (MSMs) built from the data show a gap in the implied time scales indicative of two-state folding and heterogeneous pathways connecting diffuse mesoscopic substates. Structural analysis of the 14 out of 2000 macrostates transited by the top 10 folding pathways reveals that native-like pairing between strands 1 and 2 only occurs for macrostates with pfold > 0.5, suggesting β12 hairpin formation may be rate-limiting. We believe that using simulation data such as these to seed adaptive resampling simulations will be a promising new method for achieving statistically converged descriptions of folding landscapes at longer time scales than ever before.

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    Detailed description of simulation methods, results, analysis, and Supporting Figures S1−S7. This material is available free of charge via the Internet at http://pubs.acs.org.

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