Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein.

G protein-coupled receptors (GPCRs) and G proteins transmit signals from hormones and neurotransmitters across cell membranes, initiating downstream signaling and modulating cellular behavior. Using advanced computer modeling and simulation, we identified atomistic-level structural, dynamic, and energetic mechanisms of norepinephrine (NE) and stimulatory G protein (G) interactions with β-adrenergic receptors (βARs), crucial GPCRs for heart function regulation and major drug targets. Our analysis revealed distinct binding behaviors of NE within βAR and βAR despite identical orthosteric binding pockets. βAR had an additional binding site, explaining variations in NE binding affinities. Simulations showed significant differences in NE dissociation pathways and receptor interactions with the G. βAR binds G more strongly, while βAR induces greater conformational changes in the α subunit of G. Furthermore, GTP and GDP binding to G may disrupt coupling between NE and βAR, as well as between βAR and G. These findings may aid in designing precise βAR-targeted drugs.