Structural Rearrangement\nof the AT1 Receptor Modulated\nby Membrane Thickness and Tension

Membrane-embedded mechanosensitive (MS) proteins, including\nion\nchannels and G-protein coupled receptors (GPCRs), are essential for\nthe transduction of external mechanical stimuli into biological signals.\nThe angiotensin II type 1 (AT1) receptor plays many important roles\nin cardiovascular regulation and is associated with diseases such\nas hypertension and congestive heart failure. The membrane-mediated\nactivation of the AT1 receptor is not well understood, despite this\nbeing one of the most widely studied GPCRs within the context of biased\nagonism. Here, we use extensive molecular dynamics (MD) simulations\nto characterize the effect of the local membrane environment on the\nactivation of the AT1 receptor. We show that membrane thickness plays\nan important role in the stability of active and inactive states of\nthe receptor, as well as the dynamic interchange between states. Furthermore,\nour simulation results show that membrane tension is effective in\ndriving large-scale structural changes in the inactive state such\nas the outward movement of transmembrane helix 6 to stabilize intermediate\nactive-like conformations. We conclude by comparing our simulation\nobservations with AlphaFold 2 predictions, as a proxy to experimental\nstructures, to provide a framework for how membrane mediated stimuli\ncan facilitate activation of the AT1 receptor through the β-arrestin\nsignaling pathway.