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 β 1 AR and β 2 AR despite identical orthosteric binding pockets. β 2 AR 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 . β 1 AR binds G s more strongly, while β 2 AR 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.