Non-Equilibrium Molecular Dynamics To Simulate Shear Stress On Angiotensin Ii Type 1 (At1) Receptor

AT1 is a G protein-coupled receptor responsible for controlling blood pressure in the cardiovascular system. The binding of angiotensin II (AngII) causes Gq recruitment, while shear stress (SS) activates AT1 and causes ERK1/2 phosphorylation independently of Gαq. In order to investigate the latter, atomistic non-equilibrium molecular dynamics simulations explored AT1 conformational changes under SS. The complete structure of AT1 inserted in a POPC bilayer and solvated in water, was simulated for 1 μs at 1 bar and 310 K. SS was applied deforming the simulation box separately in the x and y directions for 100 ns, at a rate of 1 pm/ps. AT1 without SS presents increased flexibility in the intracellular loop (ICL) 2, ICL 3, and helix 8. The root mean square fluctuation of the C-terminal (Leu317-Glu359) is higher without SS (0.61-1.64 nm) versus SS (0.32-0.76 nm). The radius of gyration of the C-terminal is smaller without SS (1.04-1.19 nm) compared to SS (1.36-1.40 nm), suggesting this region is more extended under SS. C-terminal is also more exposed to water in SS, as the average solvent accessible surface area is higher (44.5± 2.2 nm²) compared to AT1 without SS (38.5±1.6 nm²), including the residues prone to phosporylation by GRK (Thr332-Ser338). Collectively, the findings suggest SS exposes and makes the C-terminal more stable to GRK binding, leading to β-arrestin recruitment and, ultimately, ERK1/2 phosphorylation.