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

S. Banu Ozkan, Ivet Bahar, Ken A. Dill

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)765-769
Number of pages5
JournalNature Structural Biology
Issue number9
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics


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