GABAA (γ-aminobutyric acid type A) receptors are ligand-gated ion channels mediating fast inhibitory transmission in the mammalian brain. Here we report the molecular and electronic mechanism governing the turn-on emission of a fluorescein-based imaging probe able to target the human GABAA receptor. Multiscale calculations evidence a drastic conformational change of the probe from folded in solution to extended upon binding to the receptor. Intramolecular ππ-stacking interactions present in the folded probe are responsible for quenching fluorescence in solution. In contrast, unfolding within the GABAA receptor changes the nature of the bright excited state triggering emission. Remarkably, this turn-on effect only manifests for the dianionic prototropic form of the imaging probe, which is found to be the strongest binder to the GABAA receptor. This study is expected to assist the design of new photoactivatable screening tools for allosteric modulators of the GABAA receptor.
A fluorescein‐based imaging probe turns‐on upon binding to the human γ‐aminobutyric acid type A (GABAA) receptor. Multiscale calculations show that fluorescence is due to the rod‐like conformation of the probe within the receptor. In contrast, intramolecular ππ‐stacking interactions in the folded conformation present in solution quench emission.
Keywords: Charge Transfer States; Fluorescent Probe; GABA-a Receptor; Gabazine; QM/MM.
© 2022 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.