Interplay between the folding mechanism and binding modes in folding coupled to binding processes

Area of Science:

• Biophysics
• Structural Biology
• Computational Biology

Background:

• Proteins that fold upon partner binding display complex behaviors like induced-fit.
• The relationship between protein folding mechanisms and binding modes is not fully understood.

Purpose of the Study:

• To investigate the binding mechanism of the fast-folding, partially disordered PSBD to the E1 subunit of pyruvate dehydrogenase.
• To elucidate the role of folding dynamics (two-state vs. downhill) in protein-protein complex formation.

Main Methods:

• Utilized coarse-grained simulations to model the binding process.
• Compared binding behavior under two distinct folding scenarios: two-state and downhill folding.

Main Results:

• Induced-fit binding necessitates that PSBD undergoes folding and unfolding within the downhill folding regime.
• Proteins following a two-state folding pathway must fully fold before binding can occur.
• Partially folded conformations, crucial for coupling folding and binding, are predominantly populated in the downhill folding scenario.

Conclusions:

• Established a direct mechanistic link between induced-fit complex binding and downhill protein folding.
• Suggests that PSBD functions as a conformational rheostat, regulating binding through its folding dynamics.