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

         The Paper of the Day describes a computational approach using coarse-grained molecular dynamics (CG/MD) simulations to study the allosteric binding of cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) to the glycine receptor (GlyR). The simulations reveal that cannabinoids can bind to both intrasubunit and intersubunit sites in the transmembrane domain of the receptor. The intrasubunit binding mode for THC matches experimental cryo-EM structures, while the intersubunit binding mode is consistent with previous mutagenesis data. For AEA, the simulations predict binding to the same intersubunit site as well as an additional upper intersubunit site. These predictions are validated through electrophysiology experiments on rationally designed GlyR mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and demonstrate the effectiveness of the combined CG/MD and experimental approach for identifying and characterizing allosteric binding sites in transmembrane proteins.