Induced Fit Is a Special Case of Conformational Selection

Conformational selection (CS) and induced fit (IF) are two widely used interpretations of binding of a ligand to biological macromolecules. Both mechanisms envision a two-step reaction in which a conformational transition either precedes (CS) or follows (IF) the binding step. Under pseudo-first-order conditions where the ligand is in excess compared to the macromolecule, both mechanisms produce two relaxations. A fast one eventually increases linearly with ligand concentration and reflects the binding interaction. A slow one saturates to a constant value after decreasing or increasing hyperbolically with ligand concentration. This relaxation is the one most often accessible to experimental measurements and is potentially diagnostic of the mechanism involved. A relaxation that decreases unequivocally identifies CS, but a hyperbolic increase is compatible with both CS and IF. The potential ambiguity between the two mechanisms is more than qualitative. Here we show that the entire kinetic repertoire of IF is nothing but a mathematical special case of CS as revealed by a simple transformation of the rate constants, which emphasizes the need for independent support of either mechanism from additional experimental evidence. We discuss a simple strategy for distinguishing between IF and CS under the most common conditions encountered in practice, i.e., when the ligand is in excess compared to the macromolecule and a single relaxation is accessible to experimental measurements.