Local interactions and the optimization of protein folding

Area of Science:

• Biophysics
• Computational Biology
• Protein Dynamics

Background:

• The role of local interactions in protein folding is debated.
• Previous models often simplified the interplay between local and nonlocal forces.

Purpose of the Study:

• To investigate how local and nonlocal interactions affect protein folding kinetics and thermodynamics.
• To analyze the impact of varying local interaction contributions on folding energy landscapes.

Main Methods:

• Extended Zwanzig's folding model to include local and nonlocal interactions.
• Studied folding kinetics and thermodynamics across a range of energy functions.
• Analyzed funnel-shaped energy landscapes and protein contact distributions.

Main Results:

• Folding rate increases with local interaction strength, but stability decreases.
• Native structure content in unfolded and transition states varies with local interaction strength.
• Nonlocal interactions are crucial for simple exponential kinetics and a defined free energy barrier.
• Bumps in the folding funnel can decrease folding rates at high local interaction strengths.

Conclusions:

• Protein folding is influenced by a complex balance of local and nonlocal interactions.
• Evolutionary optimization appears to favor strong contacts that optimize both folding kinetics and thermodynamics.
• The findings provide insights into the physical principles governing protein structure formation.