Issue 14, 2023

Lipid oxidation controls peptide self-assembly near membranes through a surface attraction mechanism

Abstract

The self-assembly of peptides into supramolecular structures has been linked to neurodegenerative diseases but has also been observed in functional roles. Peptides are physiologically exposed to crowded environments of biomacromolecules, and particularly cellular membrane lipids. Previous research has shown that membranes can both accelerate and inhibit peptide self-assembly. Here, we studied the impact of membrane models 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. We found that electrostatic interactions are a primary driving force for peptide-membrane interaction, enabling us to propose a model for predicting how cellular changes might impact peptide self-assembly in vivo.

Graphical abstract: Lipid oxidation controls peptide self-assembly near membranes through a surface attraction mechanism

Supplementary files

Article information

Article type
Edge Article
Submitted
10 jan 2023
Accepted
17 feb 2023
First published
02 mar 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 3730-3741

Lipid oxidation controls peptide self-assembly near membranes through a surface attraction mechanism

T. John, S. Piantavigna, T. J. A. Dealey, B. Abel, H. J. Risselada and L. L. Martin, Chem. Sci., 2023, 14, 3730 DOI: 10.1039/D3SC00159H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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