Essential role of conformational selection in ligand binding

Area of Science:

• Biochemistry
• Molecular Biology
• Chemical Kinetics

Background:

• Ligand recognition in biological macromolecules is explained by two main mechanisms: conformational selection and induced fit.
• Conformational selection: ligand binds to pre-existing macromolecule conformations.
• Induced fit: ligand binding induces conformational changes in the macromolecule.

Purpose of the Study:

• To re-evaluate the prevailing understanding of ligand binding mechanisms.
• To analyze the kinetic criteria used to distinguish between conformational selection and induced fit.
• To determine the necessity and sufficiency of each mechanism in explaining experimental data.

Main Methods:

• Analysis of kinetic data, specifically the rate of relaxation to equilibrium (kobs) as a function of ligand concentration ([L]).
• Theoretical modeling of binding kinetics under different mechanistic assumptions.
• Comparison of kinetic predictions with existing experimental observations.

Main Results:

• The traditional kinetic criterion for distinguishing mechanisms is only valid under specific, often unrealistic, assumptions.
• Conformational selection can explain a wider range of kinetic behaviors (kobs increasing, decreasing, or independent of [L]).
• Induced fit kinetics are more limited, typically showing kobs increasing with [L].

Conclusions:

• Conformational selection is a versatile and often necessary mechanism for ligand binding kinetics.
• Induced fit is less frequently necessary and only sufficient in limited cases.
• The dominance of induced fit in explaining ligand binding should be reconsidered in favor of conformational selection.