BPS2026 – Tail-asymmetric lipids modulate membrane elasticity and permeability

Tail-length asymmetric lipids impact phase transitions of membranes and oxygen adaptability of organisms, as shown in yeast (Panconi et al. (2023). J. Biol. Chem. 299(9), 105134). The pathogenic gram-negative bacterium Francisella tularensis ( Ft ) expresses highly tail-asymmetric phosphatidylethanolamine (PE) 24:0/10:0 lipids, which suppress host cell inflammatory responses. We propose that Ft exploits lipid tail asymmetry to promote vesicle fusion and destabilize host membranes. Compared to well-characterized yeast lipids, Ft PE lipids show more significant asymmetry in their acyl tails, but the impact of tail-asymmetric Ft PE lipids on membrane morphology, phase behavior, elasticity, and permeability remains poorly understood. Here, we combine small angle X-ray scattering and molecular dynamics simulations to systematically investigate the impact of Ft PE lipids on membrane structure and properties. Increasing Ft PE content in DOPC or POPC membranes induces tighter lipid packing, slight membrane thickening, and a pronounced tendency toward gel-phase formation. When incorporated symmetrically, the long sn1 tails of Ft PE lipids extend into the opposing leaflet, driving interdigitation and balancing lipid packing between the leaflets. Asymmetric incorporation favors tail bending within the same leaflet, altering lipid packing and membrane elasticity. We further quantify free-energy costs of permeating small molecule across membranes with and without Ft PE lipids in order to understand the impact of bidirectional tail configurations of Ft PE lipids on membrane permeability. These findings provide mechanistic insight into how tail-asymmetric Ft lipids can contribute to host-pathogen interactions. This research was supported by Laboratory Directed Research and Development at Lawrence Livermore National Laboratory (24-ERD-027) and performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.