Lipid Peroxidation Modulates AT₁R Activation through Site-Specific Lipid-Protein Hydrogen Bonds and Membrane...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Oxidative stress alters cell membrane composition through lipid peroxidation.
• The impact of specific lipid peroxidation products on G protein-coupled receptor (GPCR) activation is not well understood.
• The Angiotensin II type 1 receptor (AT1R) is a key GPCR involved in blood pressure regulation.

Purpose of the Study:

• To investigate how different lipid peroxidation products affect the conformational dynamics and activation of the AT1R.
• To elucidate the molecular mechanisms by which oxidized lipids modulate GPCR signaling.

Main Methods:

• Microsecond-scale all-atom molecular dynamics simulations were employed.
• Simulations included AT1R embedded in membranes with varying degrees and positions of phospholipid peroxidation (nonperoxidized, monohydroperoxidized, dihydroperoxidized).
• Quantitative analysis of receptor conformational dynamics and lipid-protein interactions was performed.

Main Results:

• Lipid peroxidation effects depend on oxidation depth (C9 vs. C13) and degree (mono vs. di).
• Dihydroperoxidation at C13 (O13x2) promoted an active-like AT1R conformation.
• Monohydroperoxidation led to restricted receptor dynamics.
• A "polar anchor" mechanism involving hydrogen bonds between hydroperoxides and Asn5.43 was identified in O13x2 systems.

Conclusions:

• Oxidative lipid modification acts as a chemical signal modulating AT1R signaling.
• Specific lipid-protein interactions and membrane remodeling are key mechanisms.
• Findings suggest a novel pathway for GPCR regulation by oxidized lipids.