Aquaporin-4 mediated RONS transport under membrane lipid peroxidation: Atomic-scale mechanistic insights

Aquaporin-4 (AQP4) is a biological macromolecules that primarily mediates water transport across biological membranes and, under specific conditions, may also permit the passage of certain reactive oxygen and nitrogen species (RONS), thereby contributing to the regulation of intracellular and extracellular redox balance. Recent studies have shown that therapeutic strategies involving oxidative stress are frequently accompanied by elevated RONS levels and lipid peroxidation of cellular membranes; however, how peroxidized lipid derivatives derived from POPC and POPE affect the structural properties of AQP4 and its associated transmembrane behavior remains poorly understood. In this study, we employed molecular dynamics simulations, free energy calculations, and computational electrophysiology to study the effects of different degrees of lipid peroxidation on AQP4-associated RONS transport behavior. Our results indicate that lipid peroxidation alters AQP4-lipid interactions and the local membrane microenvironment, thereby modulating the propensity of RONS molecules to access and traverse key regions of the AQP4 channel. These findings highlight the role of lipid-protein interactions under oxidative conditions in shaping channel associated transmembrane processes and provide a mechanistic framework for understanding redox-related transport phenomena.