A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1

Alessio Bartocci, Andrea Grazzi, Nour Awad, Pierre-Jean Corringer, Paulo C. T. Souza and Marco Cecchini ()
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Alessio Bartocci: Université de Strasbourg
Andrea Grazzi: Université de Strasbourg
Nour Awad: Université de Paris, CNRS UMR3571
Pierre-Jean Corringer: Université de Paris, CNRS UMR3571
Paulo C. T. Souza: Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon
Marco Cecchini: Université de Strasbourg

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Glycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) potentiate the GlyR response but their mechanism of action is not fully established. By combining millisecond coarse-grained (CG) MD simulations powered by Martini 3 with backmapping to all-atom representations, we have characterized the cannabinoid-binding site(s) at the zebrafish GlyR-α1 active state with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind to the transmembrane domain of the receptor at both intrasubunit and intersubunit sites. For THC, the intrasubunit binding mode predicted in simulation is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Intriguingly, AEA is predicted to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the ligand-receptor interactions highlight potentially relevant residues for GlyR potentiation, offering experimentally testable predictions. The predictions for AEA have been validated by electrophysiology recordings of rationally designed mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and put forward an effective strategy for the identification and structural characterization of allosteric binding sites.

Date: 2024
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DOI: 10.1038/s41467-024-53098-4

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