Relative contributions of conformational selection and induced fit

A long standing debate in biochemistry is to determine whether the conformational changes observed during biomolecular interactions proceed through conformational selection (of preexisting isoforms) or induced fit (ligand-induced 3D reshaping). The latter mechanism had been invoked in certain circumstances, for example to explain the non-Michaelian activity of monomeric enzymes like glucokinase. But the relative importance of induced fit has been recently depreciated in favor of conformational selection, assumed to be always sufficient, predominant in general and in particular for glucokinase. This question is reconsidered here in the light of earlier concepts such as the cyclic equilibrium rule and the turning wheel of Wyman, in and out of equilibrium, using single molecule state probability, one way fluxes and net fluxes. The conditions for a switch from conformational selection to induced fit at a given ligand concentration are explicited. Out of equilibrium, the inspection of the enzyme states circuit shows that conformational selection alone would give a Michaelian reaction rate but not the established nonlinear behavior of glucokinase. Moreover, when induced fit and conformational selection coexist and allow kinetic cooperativity, the net flux emerging in the linkage cycle is necessarily oriented in the direction of the induced fit path.