Unifying Constraints Linking Protein Folding and Native Dynamics Decoded from AlphaFold

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• The relationship between protein folding pathways and their native functional dynamics is a fundamental biophysics problem.
• Understanding how protein structure relates to flexibility is key to deciphering protein function and evolution.

Purpose of the Study:

• To investigate the link between protein folding topology (contact order) and native dynamics (fluctuation entropy).
• To explore how this relationship varies across different protein sizes and taxonomic groups.
• To examine the impact of organismal complexity on protein structural properties.

Main Methods:

• Analysis of a large dataset of AlphaFold-predicted protein structures.
• Application of scaling analysis to identify power-law trends.
• Comparison of folding topology and dynamics metrics across diverse species.

Main Results:

• A robust correlation was found between higher contact order (slower folding) and lower fluctuation entropy (restricted dynamics).
• This relationship holds true across various protein sizes and taxonomic groups, indicating conserved principles.
• Proteome-wide analysis revealed shifts towards lower contact order and higher fluctuation entropy with increasing organismal complexity.
• Scaling analysis supports power-law-like trends, suggesting common architectural constraints.

Conclusions:

• Protein folding topology and native dynamics are intrinsically linked, governed by underlying physical constraints.
• AI-predicted structures effectively capture these fundamental principles of protein architecture.
• Evolutionary trends in organismal complexity correlate with specific shifts in protein structural dynamics.