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Updated: Jan 7, 2026

Cell-free Biochemical Fluorometric Enzymatic Assay for High-throughput Measurement of Lipid Peroxidation in High Density Lipoprotein
Published on: October 12, 2017
Lipid Peroxidation Modulates AT1R Activation through Site-Specific Lipid-Protein Hydrogen Bonds and Membrane
Ying Zhu1, Yiyang Zhang2, Zhengxi Qian1
1Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Kuang Yaming Honors School, Nanjing University, Nanjing 210023, China.
Abstract:
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-sn-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 Asn5.43 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.
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