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

Nature Structural Biology volume 8, pages 765–769 (2001)Cite this article

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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Figure 1: Folding kinetics of a lattice model chain.
Figure 2: A negative Φ-value is defined as an acceleration of folding following a destabilizing mutation.
Figure 3: Landscape mapping.
Figure 4: Correlation of Φ with τmut and τwt.

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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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Authors and Affiliations

  1. Department of Chemical Engineering, Polymer Research Center, Bogazici University, Istanbul, 80815, Bebek, 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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  1. S. Banu Ozkan
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Correspondence to Ken A. Dill.

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Ozkan, S., Bahar, I. & Dill, K. Transition states and the meaning of Φ-values in protein folding kinetics. Nat Struct Mol Biol 8, 765–769 (2001). https://doi.org/10.1038/nsb0901-765

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