Feng, Zhiwei; Hou, Tingjun; Li, Youyong
Studies on the Interactions between beta(2) Adrenergic Receptor and Gs Protein by Molecular Dynamics Simulations
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 52:1005-1014, APR 2012

The beta(2) adrenergic receptor (beta(2)AR) 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 beta(2)AR-Gs protein complex was reported, which facilitates study of the activation mechanism of the beta(2)AR and G-protein-coupled receptors (GPCRs). In this work, we perform 20 ns molecular dynamics (MD) simulations of the beta(2)AR-Gs protein complex with its agonist in an explicit lipid and water environment to investigate the activation mechanism of beta(2)AR We find that during 20 ns MD simulation with a nanobody bound the interaction between the beta(2)AR 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 beta(2)AR 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 beta(2)AR-Gs protein complex makes conformational changes in the following sequence: (1) an agonist-bound part of beta(2)AR, (2) the intracellular region of beta(2)AR, and (3) the Gs protein.

DOI:10.1021/ci200594d

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