Theory for protein folding cooperativity: helix bundles

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Protein folding stability and cooperativity are crucial for protein function.
• Previous models have not fully explained the high cooperativity observed in helix-bundle protein folding.

Purpose of the Study:

• To develop a theoretical framework for protein folding stability and cooperativity in helix-bundle proteins.
• To reconcile theoretical predictions with experimental observations of protein folding.

Main Methods:

• A Schellman-Zimm-Bragg-like approach was used to model individual helices.
• Hydrophobic and van der Waals contacts between helices were treated as a binding equilibrium.
• The model was validated against experimental data for thermal and urea-induced transitions.

Main Results:

• Predictions showed good agreement with experimental data for single helix-to-coil transitions and three-helix-bundle proteins.
• The model correctly predicts two-state cooperativities (DeltaH(van't Hoff)/DeltaH(cal) ≈ 1) for helix-bundle proteins.
• Predicted folding cooperativity exceeds that of helix formation or collapse alone due to nonlinear coupling.

Conclusions:

• The developed theory provides an accurate description of protein folding stability and cooperativity in helix bundles.
• The model successfully addresses the discrepancy in predicted versus observed protein folding cooperativity.
• Nonlinear coupling between tertiary and helical interactions enhances cooperativity in helix-bundle proteins.