Smooth functional transition along a mutational pathway with an abrupt protein fold switch

Area of Science:

• Computational biophysics
• Protein design
• Evolutionary biology

Background:

• Proteins can evolve new structures and functions through mutations.
• Understanding the pathways of protein evolution is crucial for protein design and synthetic biology.

Purpose of the Study:

• To investigate the biophysical mechanisms of protein fold transitions using a computational model.
• To explore the relationship between sequence, structure, and function during protein evolution.

Main Methods:

• Utilized a three-letter continuous protein model with explicit atomistic detail.
• Simulated folding and binding interactions for model protein sequences.
• Identified mutational pathways between distinct protein folds (alpha-helix and beta-hairpin).

Main Results:

• A sharp switch in protein fold was observed along a specific mutational pathway.
• The transition in protein binding function was gradual, not abrupt.
• The change in preferred binding partner did not align with the fold switch event.

Conclusions:

• Protein fold transitions can occur abruptly without intermediate non-functional states.
• Functional transitions are smoother than structural transitions, decoupling fold and function switching.
• Binding-induced conformational changes may guide evolutionary pathways toward novel protein folds.