[Folding@home] Simple few-state models reveal hidden complexity in protein folding

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Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17807-13. doi: 10.1073/pnas.1201810109. Epub 2012 Jul 9. ABSTRACT Markov state models constructed from molecular dynamics simulations have recently shown success at modeling protein folding kinetics. Here we introduce two methods, flux PCCA+ (FPCCA+) and sliding constraint rate estimation (SCRE), that allow accurate rate models from protein folding simulations. We apply these techniques to fourteen massive simulation datasets generated by Anton and Folding@home. Our protocol quantitatively identifies the suitability of describing each system using two-state kinetics and predicts experimentally detectable deviations from two-state behavior. An analysis of the villin headpiece and FiP35 WW domain detects multiple native substates that are consistent with experimental...

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