Functional consequences of plasmalogens - Membrane curvature and lipid miscibility

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Abstract. Functional consequences of plasmalogens—Membrane curvature and lipid miscibility Phosphatidylethanolamine plasmalogen (PEp) is prevalent in mammalian membranes, comprising 20 mol% of phospholipids in the inner leaflet of the plasma membrane (PM) according to recent lipidomics. Despite its prevalence, surprisingly little is known about its biophysical effects on biological membranes. The chemically unique vinyl ether linkage between the glycerol backbone and sn-1 fatty acyl chain is known to increase membrane fluidity and curvature; yet, PEp partitions into more structured cholesterol rich regions of the plasma membrane. Its unique curvature properties and roles in endocytic pathways and cellular signaling suggest it disrupts membrane integrity to promote fusion and fission. The proposed research combines all-atom molecular dynamics (MD) with FRET imaging and membrane fusion assays to quantify the curvature properties of pure PEp and characterize biologically relevant PEp mixtures. The proposal is for an F32 individual training fellowship. As a graduate student, trainee Dr. Alison Leonard (AL) developed an all-atom force field for PEp which she will use in the MD simulations. Whereas AL's graduate research focused on the development of lipid force field parameters and modeling of single-component membranes, the central hypothesis of this proposal addresses a topic with direct application to human health, the mechanisms of lipid homeostasis. AL will expand her knowledge of cell biology and theoretical modeling of biologically relevant lipid mixtures.