TY - JOUR T1 - Lipid Oxidation Controls Peptide Self-Assembly near Membranes JF - bioRxiv DO - 10.1101/2022.08.02.502408 SP - 2022.08.02.502408 AU - Torsten John AU - Stefania Piantavigna AU - Tiara J. A. Dealey AU - Bernd Abel AU - Herre Jelger Risselada AU - Lisandra L. Martin Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/08/03/2022.08.02.502408.abstract N2 - The self-assembly of peptides into supramolecular fibril structures has been linked to neurodegenerative diseases such as Alzheimer’s disease but has also been observed in functional roles. Peptides are physiologically exposed to crowded environments of biomacromolecules, and particularly membrane lipids, within a cellular milieu. Previous research has shown that membranes can both accelerate and inhibit peptide self-assembly. Here, we studied the impact of biomimetic membranes that mimic cellular oxidative stress and compared this to mammalian and bacterial membranes. Using molecular dynamics simulations and experiments, we propose a model that explains how changes in peptide-membrane binding, electrostatics, and peptide secondary structure stabilization determine the nature of peptide self-assembly. We explored the influence of zwitterionic (POPC), anionic (POPG) and oxidized (PazePC) phospholipids, as well as cholesterol, and mixtures thereof, on the self-assembly kinetics of the amyloid β (1–40) peptide (Aβ40), linked to Alzheimer’s disease, and the amyloid-forming antimicrobial peptide uperin 3.5 (U3.5). We show that the presence of an oxidized lipid had similar effects on peptide self-assembly as the bacterial mimetic membrane. While Aβ40 fibril formation was accelerated, U3.5 aggregation was inhibited by the same lipids at the same peptide-to-lipid ratio. We attribute these findings and peptide-specific effects to differences in peptide-membrane adsorption with U3.5 being more strongly bound to the membrane surface and stabilized in an α-helical conformation compared to Aβ40. Different peptide-to-lipid ratios resulted in different effects. Molecular dynamics simulations provided detailed mechanistic insights into the peptide-lipid interactions and secondary structure stability. We found that electrostatic interactions are a primary driving force for peptide-membrane interaction, enabling us to propose a model for predictions how cellular changes might impact peptide self-assembly in vivo, and potentially impact related diseases.Competing Interest StatementThe authors have declared no competing interest.Aβ40amyloid β (1-40)AMPantimicrobial peptideCDcircular dichroismCMCcritical micelle concentrationDLSdynamic light scatteringDMPG1,2-dimyristoyl-sn-glycero-3-phospho-(1’-rac-glycerol)MDmolecular dynamicsPazePC1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholinePBSphosphate-buffered saline: POPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholinePOPG1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1’-rac-glycerol)QCMquartz crystal microbalanceTFE2,2,2-trifluoroethanolThTthioflavin T; U3.5, uperin 3.5 ER -