Lipid Peroxidation Modulates AT ₁ R Activation through Site-Specific Lipid–Protein Hydrogen Bonds and Membrane Reorganization

Oxidative stress reshapes the chemical landscape of cell membranes, yet how specific lipid peroxidation products influence G protein-coupled receptor (GPCR) activation remains poorly understood. Here, we performed microsecond-scale all-atom molecular dynamics simulations of the Angiotensin II type 1 receptor (AT₁R) embedded in 1,2-dilinoleoyl-<i>sn</i>-glycero-3-phosphocholine (DUPC) membranes containing nonperoxidized, monohydroperoxidized (O9, O13), and dihydroperoxidized (O9 × 2, O13 × 2) phospholipids. Quantitative analysis of conformational dynamics reveals that the effects of peroxidation depend on both the depth (C9 versus C13) and degree (mono versus di) of oxidation. In these simulations, dihydroperoxidation at the C13 position (O13 × 2) enriches an active-like conformational ensemble that is more similar to that observed for an Angiotensin II-stabilized active reference than in the other membrane environments. In contrast, monohydroperoxidized membranes trap the receptor in restricted conformational subspaces with slower exchange dynamics. Mechanistically, we identify a "polar anchor" effect in O13 × 2 systems, where hydroperoxide groups form persistent hydrogen bonds with Asn^5.43 at the TM5-TM6 interface, thereby linking specific lipid-protein interactions to global conformational shifts. These findings suggest that oxidative lipid modification acts as a distinct chemical signal that can modulate AT₁R signaling through coupled local chemical interactions and global membrane remodeling.