Assessing the effect of dynamics on the closed-loop protein-folding hypothesis

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• The closed-loop (loop-n-lock) hypothesis posits that ~25-residue loops, stabilized by interactions at their ends (locks), are critical for protein structure.
• Previous research linked total contact distance (TCD) to protein folding rates.

Purpose of the Study:

• To investigate the role of loop-n-lock structures in protein folding.
• To refine the correlation between TCD and folding rates by focusing on lock-interacting residues.

Main Methods:

• Coarse-grain elastic network simulations were performed.
• Loop lengths in diverse proteins were analyzed.
• Total contact distance (TCD) calculations were conducted, with and without considering all residues.
• Molecular dynamics simulations were used to analyze the protein core/nucleus.

Main Results:

• A bias towards loops of approximately 25 residues was observed.
• An improved correlation (r² = 0.76) between TCD and folding rate was found when considering only residues contacting the loop locks, compared to all residues (r² = 0.65).
• Evidence suggested a protein core/nucleus of similar size to the lock-interacting residues.

Conclusions:

• The closed-loop hypothesis is partially supported, highlighting the importance of loop-n-lock structures.
• Efficient protein folding depends on a larger set of residues than just those forming the locks.
• The original hypothesis may be too simplistic, with a broader set of residues being critical.