Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy

Benjamin Schuler, Everett A. Lipman and William A. Eaton ()
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Benjamin Schuler: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Everett A. Lipman: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
William A. Eaton: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

Nature, 2002, vol. 419, issue 6908, 743-747

Abstract: Abstract Protein folding is inherently a heterogeneous process because of the very large number of microscopic pathways that connect the myriad unfolded conformations to the unique conformation of the native structure. In a first step towards the long-range goal of describing the distribution of pathways experimentally, Förster resonance energy transfer1 (FRET) has been measured on single, freely diffusing molecules2,3,4. Here we use this method to determine properties of the free-energy surface for folding that have not been obtained from ensemble experiments. We show that single-molecule FRET measurements of a small cold-shock protein expose equilibrium collapse of the unfolded polypeptide and allow us to calculate limits on the polypeptide reconfiguration time. From these results, limits on the height of the free-energy barrier to folding are obtained that are consistent with a simple statistical mechanical model, but not with the barriers derived from simulations using molecular dynamics. Unlike the activation energy, the free-energy barrier includes the activation entropy and thus has been elusive to experimental determination for any kinetic process in solution.

Date: 2002
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DOI: 10.1038/nature01060

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