Mechanical vs. agonist induced activation in the angiotensin II type 1 receptor.

Abstract

The angiotensin II (AngII) type 1 (AT1) receptor is a member of the GPCR type A family whose function is directly linked to diseases such as hypertension and congestive heart failure. The natural agonist for the AT1 receptor is the vasoconstricting peptide AngII, yet it can also be mechanically activated by membrane stretch or shear in the absence of an agonist. Recent experiments have shown that the AT1 receptor adopts distinct active configurations depending on the chemical structure of bound agonist, which may result in different interactions with effectors such as G-proteins and beta-arrestin to produce various functional outcomes. Here, we present a systematic simulation study that characterizes the activation of the AT1 receptor under various membrane environments and mechanical stimuli. Through microsecond molecular dynamics (MD) simulations, we show that stability of the active state is highly sensitive to membrane properties such as thickness and tension. We compare membrane-mediated vs. agonist-induced activation to show that the AT1 receptor has distinct active conformations. Furthermore, we computed free energy surfaces for the ligand and membrane activate states using our previously developed locally distributed tension collective variable method. Comparison of the free energy maps shows that inactive ad various active states have unique energy landscapes. Our modeling results provide structural insights into the mechanical activation of the AT1 receptor and how it may produce different functional outcomes within the framework of biased agonism.