Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein
Yanxiao Han,
John R.D. Dawson,
Kevin R. DeMarco,
Kyle C. Rouen,
Khoa Ngo,
Slava Bekker,
Vladimir Yarov-Yarovoy,
Colleen E. Clancy,
Yang K. Xiang,
Surl-Hee Ahn,
Igor Vorobyov
Affiliations
Yanxiao Han
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Corresponding author
John R.D. Dawson
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USA
Kevin R. DeMarco
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA
Kyle C. Rouen
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USA
Khoa Ngo
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Biophysics Graduate Group, University of California, Davis, Davis, CA 95616, USA
Slava Bekker
American River College, Sacramento, CA 95841, USA
Vladimir Yarov-Yarovoy
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Department of Anesthesiology and Pain Medicine, University of California, Davis, Davis, CA 95616, USA; Center for Precision Medicine and Data Science, University of California, Davis, Davis, CA 95616, USA
Colleen E. Clancy
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Center for Precision Medicine and Data Science, University of California, Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA
Yang K. Xiang
Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA; VA Northern California Health Care System, Mather, CA 95655, USA
Surl-Hee Ahn
Department of Chemical Engineering, University of California, Davis, Davis, CA 95616, USA; Corresponding author
Igor Vorobyov
Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA; Corresponding author
Summary: 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 (Gs) 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 Gs. β1AR binds Gs more strongly, while β2AR induces greater conformational changes in the α subunit of Gs. Furthermore, GTP and GDP binding to Gs may disrupt coupling between NE and βAR, as well as between βAR and Gs. These findings may aid in designing precise βAR-targeted drugs.
