There and back again: Two views on the protein folding puzzle

Area of Science:

• Molecular Biology
• Biophysics
• Physical Chemistry

Background:

• Protein chains spontaneously form spatial structures, a process with folding times varying by 10-11 orders of magnitude.
• Understanding the rates of overcoming the free-energy barrier between unfolded (U) and natively folded (N) protein states is crucial.

Purpose of the Study:

• To describe physical theories for protein folding and unfolding rates.
• To analyze the free-energy barrier separating the native and unfolded states.
• To reconcile theoretical predictions with experimental folding time data.

Main Methods:

• Review of physical theories for overcoming the free-energy barrier in protein folding (U-to-N) and unfolding (N-to-U).
• Application of the detailed balance principle at the equilibrium point to relate forward and reverse reaction rates.
• Analysis of protein unfolding pathways to estimate folding times paradoxically.

Main Results:

• Theoretical analysis of the N-to-U transition accurately predicts the range of protein folding rates.
• Analysis of the U-to-N transition, focusing on secondary structure formation, establishes the upper limit of folding times.
• Both theoretical approaches yield consistent results and agree with experimental data.

Conclusions:

• Physical theories for protein folding and unfolding rates are consistent and align with experimental observations.
• The theories predict the maximal size of protein domains folding under thermodynamic control.
• Understanding the energy barrier is key to explaining protein folding dynamics and domain size limitations.