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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.

Simple few-state models reveal hidden complexity in protein folding.

Author information

1
Biophysics Program, Stanford University, Stanford, CA 94305, USA.

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 data. Applying the same protocol to GTT, NTL9, and protein G suggests that some beta containing proteins can form long-lived native-like states with small register shifts. Even the simplest protein systems show folding and functional dynamics involving three or more states.

PMID:
22778442
PMCID:
PMC3497769
DOI:
10.1073/pnas.1201810109
[Indexed for MEDLINE]
Free PMC Article

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