Conformational selection or induced fit? New insights from old principles

Area of Science:

• Biochemistry
• Biophysics
• Enzyme kinetics

Background:

• The debate on biomolecular interaction mechanisms centers on conformational selection versus induced fit.
• Induced fit was previously invoked for non-Michaelian enzyme activity (e.g., glucokinase), but its importance has been downplayed in favor of conformational selection.
• Recent views suggest conformational selection is always sufficient, even for enzymes like glucokinase.

Purpose of the Study:

• To re-evaluate the relative contributions of conformational selection and induced fit in biomolecular interactions.
• To determine conditions under which a switch between these mechanisms occurs.
• To analyze enzyme kinetics both in and out of equilibrium.

Main Methods:

• Application of single molecule state probability.
• Analysis of one-way and net fluxes.
• Utilizing concepts like the cyclic equilibrium rule and Wyman's turning wheel.
• Inspection of enzyme states circuits.

Main Results:

• Explicit conditions for switching between conformational selection and induced fit at specific ligand concentrations were determined.
• Out of equilibrium, conformational selection alone predicts Michaelian kinetics, insufficient to explain glucokinase's nonlinear behavior.
• When both mechanisms coexist, inducing kinetic cooperativity, the net flux follows the induced fit pathway.

Conclusions:

• Induced fit is essential for explaining non-Michaelian enzyme kinetics, particularly for enzymes like glucokinase.
• Conformational selection alone cannot account for the observed nonlinear kinetics of certain enzymes.
• The interplay between conformational selection and induced fit dictates enzyme behavior, especially under non-equilibrium conditions.