Studies on the interactions between β2 adrenergic receptor and Gs protein by molecular dynamics simulations

The β2 adrenergic receptor (β2AR) plays a key role in the control of smooth muscle relaxation in airways, the therapy of asthma, and a series of other basic physiological functions. Recently, the crystal structure of the β2AR-Gs protein complex was reported, which facilitates study of the activation mechanism of the β2AR and G-protein-coupled receptors (GPCRs). In this work, we perform 20 ns molecular dynamics (MD) simulations of the β2AR-Gs protein complex with its agonist in an explicit lipid and water environment to investigate the activation mechanism of β2AR. We find that during 20 ns MD simulation with a nanobody bound the interaction between the β2AR and the Gs protein is stable and the whole system is equilibrated within 6 ns. However, without a nanobody stabilizing the complex, the agonist triggers conformational changes of β2AR sequentially from the extracellular region to the intracellular region, especially the intracellular parts of TM3, TM5, TM6, and TM7, which directly interact with the Gs protein. Our results show that the β2AR-Gs protein complex makes conformational changes in the following sequence: (1) an agonist-bound part of β2AR, (2) the intracellular region of β2AR, and (3) the Gs protein.