Configuration-dependent diffusion dynamics of downhill and two-state protein folding

Area of Science:

• Protein dynamics
• Biophysics
• Computational chemistry

Background:

• Configuration-dependent diffusion (CDD) is critical for protein folding kinetics, particularly for proteins with small thermodynamic barriers.
• CDD's role is even more pronounced in downhill protein folding, which lacks significant thermodynamic barriers.

Purpose of the Study:

• To investigate the influence of CDD on the folding dynamics of a downhill protein (BBL) and a two-state protein (CI2).
• To reveal hidden kinetic barriers arising from CDD.
• To analyze the temperature dependence of CDD and its relation to landscape topography.

Main Methods:

• Molecular dynamics simulations
• Analysis of free-energy profiles
• Kinetic analysis of folding pathways

Main Results:

• Hidden kinetic barriers of approximately 1 k(B)T were identified due to CDD, consistent with experimental data for fast-folding proteins.
• The free-energy profile and folding kinetics of the downhill protein BBL are substantially influenced by CDD, with kinetics being diffusion-dominated.
• The temperature dependence of CDD was characterized, and a metric involving folding transition temperature and optimal kinetic folding temperature was proposed to assess landscape topography and downhill folding propensity.

Conclusions:

• CDD plays a crucial role in determining protein folding dynamics, especially in the absence of substantial thermodynamic barriers.
• The findings provide insights into the quantitative impact of diffusion on protein folding.
• The proposed temperature-based ratio serves as a valuable indicator for protein landscape features and downhill folding behavior.