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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Benjamin Schuler & Everett A. Lipman & William A. Eaton, 2002. "Probing the free-energy surface for protein folding with single-molecule fluorescence spectroscopy," Nature, Nature, vol. 419(6908), pages 743-747, October.
    • Handle: RePEc:nat:nature:v:419:y:2002:i:6908:d:10.1038_nature01060
    DOI: 10.1038/nature01060
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    Citations

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    Cited by:

    1. Martin Hoefling & Nicola Lima & Dominik Haenni & Claus A M Seidel & Benjamin Schuler & Helmut Grubmüller, 2011. "Structural Heterogeneity and Quantitative FRET Efficiency Distributions of Polyprolines through a Hybrid Atomistic Simulation and Monte Carlo Approach," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-19, May.
    2. Mark F. Nüesch & Lisa Pietrek & Erik D. Holmstrom & Daniel Nettels & Valentin Roten & Rafael Kronenberg-Tenga & Ohad Medalia & Gerhard Hummer & Benjamin Schuler, 2024. "Nanosecond chain dynamics of single-stranded nucleic acids," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Antonio B Oliveira Jr. & Francisco M Fatore & Fernando V Paulovich & Osvaldo N Oliveira Jr. & Vitor B P Leite, 2014. "Visualization of Protein Folding Funnels in Lattice Models," PLOS ONE, Public Library of Science, vol. 9(7), pages 1-9, July.
    4. Mingu Kang & Hyunwoo Kim & Elham Oleiki & Yeonjeong Koo & Hyeongwoo Lee & Huitae Joo & Jinseong Choi & Taeyong Eom & Geunsik Lee & Yung Doug Suh & Kyoung-Duck Park, 2022. "Conformational heterogeneity of molecules physisorbed on a gold surface at room temperature," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Andreas Hartmann & Koushik Sreenivasa & Mathias Schenkel & Neharika Chamachi & Philipp Schake & Georg Krainer & Michael Schlierf, 2023. "An automated single-molecule FRET platform for high-content, multiwell plate screening of biomolecular conformations and dynamics," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Ashish Joshi & Anuja Walimbe & Anamika Avni & Sandeep K. Rai & Lisha Arora & Snehasis Sarkar & Samrat Mukhopadhyay, 2023. "Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Zhaowei Liu & Haipei Liu & Andrés M. Vera & Byeongseon Yang & Philip Tinnefeld & Michael A. Nash, 2024. "Engineering an artificial catch bond using mechanical anisotropy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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