Ether linkages in phospholipids provide modular control of membrane mechanics

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.