The properties of cell-mimetic phospholipid vesicles are readily modified by adding synthetic receptors.

Phospholipids are the primary constituent of cell membranes. These amphiphiles contain two hydrophobic fatty acid tails and a hydrophilic polar head group, and when dispersed in aqueous solution they self-assemble into bilayers with the polar head groups facing outwards. These bilayers then close in on themselves to create enclosed spherical assemblies with an interior volume isolated from the exterior aqueous solution; these structures are called vesicles and are simple structural mimics of cells.

We aim to transform these vesicles in functional mimics of cells. To do so, we synthesise artificial lipids with hydrophobic tags, which anchor into the vesicle bilayer membrane, and desired molecular motifs in the headgroup: for example metal complexes, sugars or biotin.

Fluorescence microscopy image of a giant unilamellar vesicle (GUV, red membrane) with His-tagged GFP (green protein) bound to artificial lipid rafts composed of a Cu(IDA) capped fluorinated lipid (shown top)

We found that adding fluorine to the hydrophobic tag gives artificial lipids that phase separate in vesicle membranes, giving adhesive microdomains (artificial “lipid rafts”) that alter the strength of molecular recognition and reactivity with soluble enzymes.

These adhesive microdomains can strengthen multivalent molecular recognition, strengthening vesicle-vesicle adhesion and mimicking the behaviour of cell adhesion molecules. Nonetheless, the enhancement of multivalent recognition depends upon ligand geometry and the strength of the interaction between the ligand and membrane-bound receptors; strong binding can result in receptor reorganisation within the membrane.

Adhesive microdomains can also alter reactivity. We have recently reported the transfer of sialic acid by the enzyme TcTS to synthetic glycolipids embedded in phospholipid bilayers can create vesicles with a synthetic sialylated “glycocalyx”. Similarly, ß1,4-GalT1 produced vesicles with a synthetic LacNAc “glycocalyx”; when the glycolipids were phase separated into microdomains a 9-fold rate increase in the rate of catalysis by ß1,4-GalT1 resulted.

Sialylation of lactosyl lipids in membrane microdomains by T. cruzi trans-sialidase.

Noble, GT; Craven, FL; Segarra-Maset, MD; Reyes Martínez, JE; Šardzík, R; Flitsch, SL; Webb, SJ

Org. Biomol. Chem. 2014, 12, 9272-9278.

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Accelerated enzymatic galactosylation of N-acetylglucosaminolipids in lipid microdomains.

Noble, GT; Craven, FL; Voglmeir, J; Šardzík, R; Flitsch, SL; Webb, SJ

J. Am. Chem. Soc. 2012, 134, 13010-13017

Selected as a JACS "Spotlight" article in Sept. 2012.

The effect of multivalent binding on the lateral phase separation of adhesive lipids.

Liem, KP; Noble, GT; Flitsch, SL; Webb, SJ.

Faraday Discuss. 2010, 145, 219-233.

The effect of receptor clustering on vesicle-vesicle adhesion.

Mart, RJ; Liem, KP; Wang, X; Webb, SJ.

J. Am. Chem. Soc. 2006, 128, 14462-14463.