Competition between induced fit and conformational selection binding: how different flux-based approaches may help clarifying their interplay.

Abstract

BackgroundBinding kinetics has become a popular discipline in pharmacology. Yet, it was recommended a decade ago to look on ligand-target binding in terms of fluxes instead of rate constants. Like product formation in enzymology, these binding fluxes stand for the rate/velocity by which the target converts form one state into another. Several thereon-based approaches can be used for studying the functioning binding mechanisms. ObjectivesAlthough the relative contribution/importance of the induced fit and conformational selection binding pathways within a thermodynamic cycle is still hotly debated, only a single flux-based approach is customarily addressed for such calculations. There is a need to better understand the relevance of this peculiar approach. MethodsThe present findings relied on differential equation-based simulations, using the provided forward- and reverse rate constants for four reported cases as input. ResultsBoth pathways may act in unison and even in tandem rather than being mutually exclusive. Also, calculating their relative contribution by distinct flux-based approaches may yield different outcomes for some of the cases under pre-equilibrium as well as equilibrium conditions. Additional flux-based approaches offer a rationale for the occurrence of those disparities. ConclusionsThe interplay between the induced fit- and conformational selection pathways is even more intricate than hitherto expected. It may me preferable to quantitate their relative contribution in terms of target occupancies instead of binding fluxes when genuine equilibrium can be reached. PerspectivesCompared to the often-used elaborate algebraic equations, combining different binding flux-based approaches may offer better intuitive and visual insight into the functioning of complex binding mechanisms. More attention should also be paid to physiologically more relevant non-equilibrium situations.