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Transition states and the meaning of Φ-values in protein folding kinetics

Nature Structural Biology volume 8, pages 765769 (2001) | Download Citation

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Abstract

What is the mechanism of two-state protein folding? The rate-limiting step is typically explored through a Φ-value, which is the mutation-induced change in the transition state free energy divided by the change in the equilibrium free energy of folding. Φ-values ranging from 0 to 1 have been interpreted as meaning the transition state is denatured-like (0), native-like (1) or in-between. But there is no classical interpretation for the experimental Φ-values that are negative or >1. Using a rigorous method to identity transition states via an exact lattice model, we find that nonclassical Φ-values can arise from parallel microscopic flow processes, such as those in funnel-shaped energy landscapes. Φ < 0 results when a mutation destabilizes a slow flow channel, causing a backflow into a faster flow channel. Φ > 1 implies the reverse: a backflow from a fast channel into a slow one. Using a 'landscape mapping' method, we find that Φ correlates with the acceleration/deceleration of folding induced by mutations, rather than with the degree of nativeness of the transition state.

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Acknowledgements

We thank J. Schonbrun, D. Thirumalai, A. Fersht, D. Goldenberg and A. Robertson for helpful comments and the NIH for grant support. We would also like to acknowledge a TUBITAK fellowship to S.B.O. We are grateful to J. Schreurs for the preparation of the figures.

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Affiliations

  1. Department of Chemical Engineering, Polymer Research Center, Bogazici University, Bebek 80815, Istanbul, Turkey.

    • S. Banu Ozkan
  2. Department of Pharmaceutical Chemistry, University of California San Francisco, California 94143-1204, USA.

    • S. Banu Ozkan
    •  & Ken A. Dill
  3. Center for Computational Biology & Bioinformatics, and Department of Molecular Genetics & Biochemistry, School of Medicine, University of Pittsburgh, Pennsylvania 15213, USA.

    • Ivet Bahar

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Correspondence to Ken A. Dill.

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DOI

https://doi.org/10.1038/nsb0901-765

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