Local secondary structure content predicts folding rates for simple, two-state proteins

Haipeng Gong, Daniel G. Isom, Rajgopal Srinivasan, George D. Rose

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


Many single-domain proteins exhibit two-state folding kinetics, with folding rates that span more than six orders of magnitude. A quantity of much recent interest for such proteins is their contact order, the average separation in sequence between contacting residue pairs. Numerous studies have reached the surprising conclusion that contact order is well-correlated with the logarithm of the folding rate for these small, well-characterized molecules. Here, we investigate the physico-chemical basis for this finding by asking whether contact order is actually a composite number that measures the fraction of local secondary structure in the protein; viz. turns, helices, and hairpins. To pursue this question, we calculated the secondary structure content for 24 two-state proteins and obtained coefficients that predict their folding rates. The predicted rates correlate strongly with experimentally determined rates, comparable to the correlation with contact order. Further, these predicted folding rates are correlated strongly with contact order. Our results suggest that the folding rate of two-state proteins is a function of their local secondary structure content, consistent with the hierarchic model of protein folding. Accordingly, it should be possible to utilize secondary structure prediction methods to predict folding rates from sequence alone.

Original languageEnglish (US)
Pages (from-to)1149-1154
Number of pages6
JournalJournal of molecular biology
Issue number5
StatePublished - Apr 11 2003
Externally publishedYes


  • Contact order
  • Folding kinetics
  • Secondary structure
  • Two-state folding

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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