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Protein folding kinetics: barrier effects in chemical and thermal denaturation experiments

AuthorsNaganathan, Athi N. ; Doshi, Urmi; Muñoz, Víctor
KeywordsProtein folding
Folding kinetics
Downhill folding
Free energy barriers
Two-state analyses
Diffusion coefficient
Issue Date10-Apr-2007
PublisherAmerican Chemical Society
CitationJ. Am. Chem. Soc. 129(17): 5673-5682 (2007)
AbstractRecent experimental work on fast protein folding brings about an intriguing paradox. Microsecond-folding proteins are supposed to fold near or at the folding speed limit (downhill folding), but yet their folding behavior seems to comply with classical two-state analyses, which imply the crossing of high free energy barriers. However, close inspection of chemical and thermal denaturation kinetic experiments in fast-folding proteins reveals systematic deviations from two-state behavior. Using a simple one-dimensional free energy surface approach we find that such deviations are indeed diagnostic of marginal folding barriers. Furthermore, the quantitative analysis of available fast-kinetic data indicates that many microsecond-folding proteins fold downhill in native conditions. All of these proteins are then promising candidates for an atom-by-atom analysis of protein folding using nuclear magnetic resonance. We also find that the diffusion coefficient for protein folding is strongly temperature dependent, corresponding to an activation energy of ~1 kJ·mol-1 per protein residue. As a consequence, the folding speed limit at room temperature is about an order of magnitude slower than the ~ 1 μs estimates from high-temperature T-jump experiments. Our analysis is quantitatively consistent with the available thermodynamic and kinetic data on slow two-state folding proteins and provides a straightforward explanation for the apparent fast-folding paradox.
Description10 pages, 5 figures.-- PMID: 17419630 [PubMed].-- PMCID: PMC2527040.-- Author manuscript available in PMC: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17419630
Printed version published on May 2, 2007.
Publisher version (URL)http://dx.doi.org/10.1021/ja0689740
Appears in Collections:(CIB) Artículos
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