Is Protein Folding a Thermodynamically Unfavorable, Active, Energy-Dependent Process?

Area of Science:

• Biophysics
• Molecular Biology
• Protein Dynamics

Background:

• The thermodynamic hypothesis posits native protein conformation as the global free energy minimum.
• Empirical evidence supporting this hypothesis is limited.
• Current physical theories struggle to predict protein folding pathways.

Purpose of the Study:

• To challenge the prevailing thermodynamic hypothesis of protein folding.
• To propose an alternative model for protein folding mechanisms.
• To highlight the role of cellular machinery in protein folding.

Main Methods:

• Critical review of existing empirical and theoretical evidence for protein folding.
• Analysis of limitations in current physical theory-based prediction methods.
• Discussion of evolutionary modeling and deep learning successes in structure prediction.

Main Results:

• The thermodynamic hypothesis is not strongly supported by empirical data.
• Physical theories have largely failed to predict protein folds and pathways.
• Deep learning excels at structure prediction but not mechanism.
• An alternative model suggests proteins fold into local minima via cellular machinery.

Conclusions:

• The native state may be a local, not global, free energy minimum.
• Positive Gibbs free energy change (ΔG) for folding is likely for many proteins.
• In vivo folding is an active, energy-dependent process involving cellular machinery like chaperones and the translation system.
• Protein folding should be modeled as a non-equilibrium, in vivo process.