Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants

Abstract Induced fit‐ (IF) and conformational selection (CS) binding mechanisms have long been regarded to be mutually exclusive. Yet, they are now increasingly considered to produce the final ligand‐target complex alongside within a thermodynamic cycle. This viewpoint benefited from the introductio...

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Autores principales:	Georges Vauquelin, Dominique Maes
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	binding fluxes conformational selection equations induced fit rate constants simulations Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/cf1070c49534475f88ff1335da182eab
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spelling	oai:doaj.org-article:cf1070c49534475f88ff1335da182eab2021-11-16T13:45:54ZInduced fit versus conformational selection: From rate constants to fluxes… and back to rate constants2052-170710.1002/prp2.847https://doaj.org/article/cf1070c49534475f88ff1335da182eab2021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.847https://doaj.org/toc/2052-1707Abstract Induced fit‐ (IF) and conformational selection (CS) binding mechanisms have long been regarded to be mutually exclusive. Yet, they are now increasingly considered to produce the final ligand‐target complex alongside within a thermodynamic cycle. This viewpoint benefited from the introduction of binding fluxes as a tool for analyzing the overall behavior of such cycle. This study aims to provide more vivid and applicable insights into this emerging field. In this respect, combining differential equation‐ based simulations and hitherto little explored alternative modes of calculation provide concordant information about the intricate workings of such cycle. In line with previous reports, we observe that the relative contribution of IF increases with the ligand concentration at equilibrium. Yet the baseline contribution may vary from one case to another and simulations as well as calculations show that this parameter is essentially regulated by the dissociation rate of both pathways. Closer attention should be paid to how the contributions of IF and CS compare at physiologically relevant drug/ligand concentrations. To this end, a simple equation discloses how changing a limited set of “microscopic” rate constants can extend the concentration range at which CS contributes most effectively. Finally, it could also be beneficial to extend the utilization of flux‐ based approaches to more physiologically relevant time scales and alternative binding models.Georges VauquelinDominique MaesWileyarticlebinding fluxesconformational selectionequationsinduced fitrate constantssimulationsTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	binding fluxes conformational selection equations induced fit rate constants simulations Therapeutics. Pharmacology RM1-950
spellingShingle	binding fluxes conformational selection equations induced fit rate constants simulations Therapeutics. Pharmacology RM1-950 Georges Vauquelin Dominique Maes Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants
description	Abstract Induced fit‐ (IF) and conformational selection (CS) binding mechanisms have long been regarded to be mutually exclusive. Yet, they are now increasingly considered to produce the final ligand‐target complex alongside within a thermodynamic cycle. This viewpoint benefited from the introduction of binding fluxes as a tool for analyzing the overall behavior of such cycle. This study aims to provide more vivid and applicable insights into this emerging field. In this respect, combining differential equation‐ based simulations and hitherto little explored alternative modes of calculation provide concordant information about the intricate workings of such cycle. In line with previous reports, we observe that the relative contribution of IF increases with the ligand concentration at equilibrium. Yet the baseline contribution may vary from one case to another and simulations as well as calculations show that this parameter is essentially regulated by the dissociation rate of both pathways. Closer attention should be paid to how the contributions of IF and CS compare at physiologically relevant drug/ligand concentrations. To this end, a simple equation discloses how changing a limited set of “microscopic” rate constants can extend the concentration range at which CS contributes most effectively. Finally, it could also be beneficial to extend the utilization of flux‐ based approaches to more physiologically relevant time scales and alternative binding models.
format	article
author	Georges Vauquelin Dominique Maes
author_facet	Georges Vauquelin Dominique Maes
author_sort	Georges Vauquelin
title	Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants
title_short	Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants
title_full	Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants
title_fullStr	Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants
title_full_unstemmed	Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants
title_sort	induced fit versus conformational selection: from rate constants to fluxes… and back to rate constants
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/cf1070c49534475f88ff1335da182eab
work_keys_str_mv	AT georgesvauquelin inducedfitversusconformationalselectionfromrateconstantstofluxesandbacktorateconstants AT dominiquemaes inducedfitversusconformationalselectionfromrateconstantstofluxesandbacktorateconstants
_version_	1718426508312182784

Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants

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