Interplay between secondary and tertiary structure formation in protein folding cooperativity

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Protein folding cooperativity is characterized by thermodynamic transitions.
• Two-state folding involves a free-energy barrier, while downhill folding is barrierless.
• Microcanonical analysis is better suited than canonical analysis for characterizing transitions.

Purpose of the Study:

• To unambiguously characterize the nature of protein folding transitions.
• To evaluate the density of states and extract precise thermodynamic information.
• To measure the impact of thermodynamic properties on protein structural features.

Main Methods:

• Replica-exchange molecular dynamics simulations.
• High-resolution coarse-grained modeling.
• Microcanonical analysis of the density of states.

Main Results:

• A short helix exhibited two-state folding characteristics.
• A longer helix displayed downhill folding.
• A three-helix bundle showed two-state transitions.
• The interplay between secondary structure and tertiary contact loss determines transition nature.

Conclusions:

• The nature of protein folding transitions is determined by the balance between secondary structure formation and tertiary contact disruption.
• Microcanonical analysis combined with molecular dynamics simulations provides accurate thermodynamic insights into protein folding.