BPS2026 – Membrane phase behavior controlled by lipid head group composition

The role of lipid diversity in modulating material properties and functions of biological membranes is not well characterized by lipidomics studies. Phosphocholine (PC) and phosphoethanolamine (PE) are two common head groups of glycerophospholipids found in mammalian cells, which have an asymmetric distribution between the leaflets. We studied the material properties of 1,2-dioleoyl- sn -glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl- sn -glycero-3-phosphoethanolamine (DOPE) using solid-state 2 H NMR spectroscopy, with an emphasis on the phase behavior in the lamellar and reverse-hexagonal (H II ) phases. To overcome challenges in NMR investigations of di-unsaturated lipid systems, we used a tracer lipid approach to probe their average structural properties. The DOPE/DOPC mixtures demonstrated opposing effects on segmental order parameters depending on phase with a greater fraction of DOPE increasing order in the lamellar but diminishing it in the H II phase. Raising DOPE concentrations decreased the area per lipid at the lipid/water interface, leading to greater molecular packing (higher order parameters) in the lamellar phase and promoting formation of smaller cylinders in the reversed-hexagonal phase (decreased order). Importantly, DOPE/DOPC mixtures exhibited intermediate properties between pure DOPC and DOPE dependent on the relative concentrations of PC to PE, implying that lipids function as a continuous modulator of bulk lipid properties, rather than by an all-or-nothing mechanism. Validated with molecular dynamics studies, our work highlights how lipid composition controls integral membrane properties and how these compositional effects interplay with the bilayer phase, thereby connecting lipidomics to membrane function. This relationship can be applied to study membrane protein-lipid interactions as regulatory mechanisms. In future work it remains to be established how head group variety combines with other types of chemical diversity, such as acyl chain unsaturation, chain length, and sterol content to control bulk membrane properties. 1 Molugu, T.R. et al., (2022). Biophys. J . 121, 4205.