Energy landscape analysis of native folding of the prion protein yields the diffusion constant, transition path time, and rates

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DOIResolve DOI: http://doi.org/10.1073/pnas.1206190109
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TypeArticle
Journal titleProceedings of the National Academy of Sciences of the United States of America
ISSN0027-8424
1091-6490
Volume109
Issue36
Pages1445214457; # of pages: 6
Subjectkinetics; optical trapping; single molecule
AbstractProtein folding is described conceptually in terms of diffusion over a configurational free-energy landscape, typically reduced to a one-dimensional profile along a reaction coordinate. In principle, kinetic properties can be predicted directly from the landscape profile using Kramers theory for diffusive barrier crossing, including the folding rates and the transition time for crossing the barrier. Landscape theory has been widely applied to interpret the time scales for protein conformational dynamics, but protein folding rates and transition times have not been calculated directly from experimentally measured free-energy profiles. We characterized the energy landscape for native folding of the prion protein using force spectroscopy, measuring the change in extension of a single protein molecule at high resolution as it unfolded/refolded under tension. Key parameters describing the landscape profile were first recovered from the distributions of unfolding and refolding forces, allowing the diffusion constant for barrier crossing and the transition path time across the barrier to be calculated. The full landscape profile was then reconstructed from force-extension curves, revealing a double-well potential with an extended, partially unfolded transition state. The barrier height and position were consistent with the previous results. Finally, Kramers theory was used to predict the folding rates from the landscape profile, recovering the values observed experimentally both under tension and at zero force in ensemble experiments. These results demonstrate how advances in single-molecule theory and experiment are harnessing the power of landscape formalisms to describe quantitatively the mechanics of folding.
Publication date
LanguageEnglish
AffiliationSecurity and Disruptive Technologies; National Research Council Canada
Peer reviewedYes
NPARC number21269081
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Record identifier48ab5d3f-04a8-4d6e-a68a-32e8eb05ae74
Record created2013-12-05
Record modified2016-05-09
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