Year: 2026
Type: preprint
Abstract: The structures of phospholipid headgroups and chains are well-established determinants of membrane elastic properties, but functions for different chemistries that join these moieties together are poorly understood. While common phospholipids feature ester linkages, alkyl ether- and plasmenyl-linked species emerged in prokaryotes, are highly abundant in metazoans, and have been implicated in neurodegeneration and aging. Multiple pathways for ether lipid synthesis evolved convergently, suggesting conserved functions for ether linkage chemistry in the structure of cell membranes. Here we combine experiments and molecular simulations to show that backbone linkage chemistry provides modular control of membrane mechanics and topology through a set of discrete drivers. Alkyl linkages provide the first of these by additively promoting negative intrinsic curvature, which destabilizes bilayers. Ethers also decouple membrane stiffness from viscosity, softening membranes while maintaining packing in the hydrophobic core. The plasmenyl C=C bond represents a second, distinct driver that stabilizes the inverted hexagonal phase by relieving interstitial packing frustration. These results explain the fusogenicity of ether lipids, show how they regulate membrane topology through multiple physical mechanisms, and provide a rationale for convergent evolution of the complex plasmenyl linkage moiety. Significance statement The structure and dynamics of cell membranes can be sensitive to small chemical changes in their phospholipid building blocks. We describe how phospholipid backbone linkage chemistry controls membrane mechanical properties: ether linkages facilitate membrane dynamics by imposing a more conical molecular profile and by decoupling bending stiffness from chain ordering. Plasmalogen lipids, in which the ether linkage is modified with a vicinal double bond, further promote non-lamellar topologies through relief of interstitial packing frustration. These biophysical features suggest a basis for the repeated emergence of ether phospholipids in evolution and their observed functions in membrane trafficking. The thermodynamic and structural bases of plasmalogen function are especially notable as these lipids have been increasingly implicated in neurodegenerative and cardiovascular disease.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, National Aeronautics and Space Administration, Gordon and Betty Moore Foundation, National Institutes of Health, Office of Naval Research, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W7162024022