50+ Years of Protein Folding

Area of Science:

• Molecular Biology
• Biophysics
• Protein Dynamics

Background:

• Protein folding, the spontaneous formation of 3D structures, remains a central puzzle in molecular biology.
• Experimentally observed folding rates for single-domain globular proteins span an enormous range, from microseconds to hours (10-11 orders of magnitude).

Observation:

• This review synthesizes literature and personal insights on the journey to understand protein folding.
• Key focus is placed on the free-energy landscape of protein conformations, particularly the energy barrier between unfolded (U) and natively folded (N) states.

Findings:

• Physical theories for crossing the U-N barrier in both folding and unfolding directions yield consistent results.
• These theories successfully outline the experimentally observed rates for protein folding and unfolding.

Implications:

• Theories predict the maximum size of protein domains governed by thermodynamic control.
• This work explains the observed upper limit for 'foldable' protein domains based on physical principles.