Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the β2 Adrenergic Receptor.

Experiments have revealed that in the β(2) adrenergic receptor (β(2)AR)-Gs protein complex the α subunit (Gαs) of the Gs protein can adopt either an "open" conformation or a "closed" conformation. In the "open" conformation the Gs protein prefers to bind to the β(2)AR, while in the "closed" conformation an uncoupling of the Gs protein from the β(2)AR occurs. However, the mechanism that leads to such different behaviors of the Gs protein remains unclear. Here, we report results from microsecond molecular dynamics simulations and community network analysis of the β(2)AR-Gs complex with Gαs in the "open" and "closed" conformations. We observed that the complex is stabilized differently in the "open" and "closed" conformations. The community network analysis reveals that in the "closed" conformation there exists strong allosteric communication between the β(2)AR and Gβγ, mediated by Gαs. We suggest that such high information flows are necessary for the Gs protein uncoupling from the β(2)AR.