Local versus global fold switching in protein evolution: insight from a three-letter continuous model

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Proteins can alter their structural folds through point mutations.
• Fold switching can occur directly or via bistable intermediates that stabilize multiple conformations.

Purpose of the Study:

• To investigate the relationship between fold similarity and the mechanism of protein fold switching.
• To test the hypothesis that bistable intermediates are more common for structurally similar folds, while direct switches are more common for dissimilar folds.

Main Methods:

• Utilized a reduced biophysical model with seven atoms per amino acid and three amino acid types.
• Analyzed mutational pathways for fold switching between beta-hairpin and alpha-helix structures (16 amino acids).
• Examined fold switching between [Formula: see text] and [Formula: see text] structures (35 amino acids).

Main Results:

• Fold switching was observed to be a sharp process, requiring only a few mutations.
• The energy balance shift between native states drives the sharpness of mutationally induced fold switching.
• Conformational entropy influences the precise point of fold switching along a mutational pathway.

Conclusions:

• The mechanism of protein fold switching (direct vs. bistable intermediate) is influenced by the structural similarity of the target folds.
• Energy balance and conformational entropy are key factors governing mutationally driven protein fold switching.