A theoretical search for folding/unfolding nuclei in three-dimensional protein structures

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Protein folding and unfolding involve transient, half-folded microstates.
• Experimentally observing these microstates is challenging, especially in two-state transitions.
• The transition state ensemble significantly influences protein folding/unfolding kinetics.

Purpose of the Study:

• To computationally determine the semifolded microstates (transition states) of proteins.
• To utilize the provided three-dimensional protein structure for these calculations.
• To investigate the relationship between protein structure and folding kinetics.

Main Methods:

• Developed an approach based on the capillarity theory of protein folding and unfolding.
• Employed a search for free-energy saddle points on a network of protein unfolding pathways.
• Utilized dynamic programming for efficient computation of these pathways.

Main Results:

• Computed folding nuclei resemble compact, closely packed regions of the native fold with few disordered loops.
• The estimated free energy of these nuclei aligns with rapid folding/unfolding kinetics of small proteins.
• The method shows good correlation with experimental observations.

Conclusions:

• The capillarity theory-based approach effectively predicts protein folding nuclei.
• Identified structures of transition states provide insights into folding mechanisms.
• This computational method offers a valuable tool for understanding protein dynamics.