ArticlePredicting repeat protein folding kinetics from an experimentally determined folding energy landscape |
| Timothy O. Street 1, Doug Barrick 2 * |
1Department of Biochemistry and Biophysics and the Howard Hughes Medical Institute, University of California, San Francisco, California 94158-2517
2T.C. Jenkins Department of Biophysics, Johns Hopkins University, Jenkins Hall, Baltimore, Maryland 21218
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| email: Doug Barrick (barrick@jhu.edu) |
*Correspondence to Doug Barrick, Department of Biophysics, Johns Hopkins University, Jenkins Hall, 3400 North Charles Street, Baltimore, MD 21218
Funded by:
Burroughs Welcome Predoctoral Fellowship
NIH; Grant Number: 1RO1 GM068462
| repeat protein protein folding energy landscape folding kinetics |
| The Notch ankyrin domain is a repeat protein whose folding has been characterized through equilibrium and kinetic measurements. In previous work, equilibrium folding free energies of truncated constructs were used to generate an experimentally determined folding energy landscape (Mello and Barrick, Proc Natl Acad Sci USA 2004;101:14102-14107). Here, this folding energy landscape is used to parameterize a kinetic model in which local transition probabilities between partly folded states are based on energy values from the landscape. The landscape-based model correctly predicts highly diverse experimentally determined folding kinetics of the Notch ankyrin domain and sequence variants. These predictions include monophasic folding and biphasic unfolding, curvature in the unfolding limb of the chevron plot, population of a transient unfolding intermediate, relative folding rates of 19 variants spanning three orders of magnitude, and a change in the folding pathway that results from C-terminal stabilization. These findings indicate that the folding pathway(s) of the Notch ankyrin domain are thermodynamically selected: the primary determinants of kinetic behavior can be simply deduced from the local stability of individual repeats. |
Received: 25 August 2008; Revised: 30 September 2008; Accepted: 13 October 2008
10.1002/pro.9
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