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_s) 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 β₁AR and β₂AR despite identical orthosteric binding pockets. β₂AR 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_s. β₁AR binds G_s more strongly, while β₂AR induces greater conformational changes in the α subunit of G_s. Furthermore, GTP and GDP binding to G_s may disrupt coupling between NE and βAR, as well as between βAR and G_s. These findings may aid in designing precise βAR-targeted drugs.