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

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Single-domain proteins often exhibit two-state folding kinetics.
• Folding rates vary significantly, with contact order (average sequence separation of contacts) showing a strong correlation with folding rate.
• The underlying physical basis for this correlation remains an area of active investigation.

Purpose of the Study:

• To investigate the physico-chemical basis of the correlation between contact order and protein folding rates.
• To determine if contact order is a composite measure reflecting local secondary structure content (turns, helices, hairpins).
• To assess the predictive power of secondary structure content for protein folding rates.

Main Methods:

• Calculated secondary structure content for 24 two-state proteins.
• Derived coefficients to predict folding rates based on secondary structure content.
• Compared predicted folding rates with experimentally determined rates and contact order correlations.

Main Results:

• Predicted folding rates based on secondary structure content correlated strongly with experimentally determined rates.
• These predicted rates showed a strong correlation with contact order.
• The predictive accuracy was comparable to that of contact order itself.

Conclusions:

• Protein folding rate in two-state proteins is a function of local secondary structure content.
• This finding supports the hierarchic model of protein folding.
• Secondary structure prediction methods can potentially predict folding rates directly from amino acid sequence.