Molecular engineering of protein-lipid interactions for immunotherapy

Biological membranes display exquisite organisation, in part through the formation of highly ordered lipid microdomains (or "lipid rafts"). Lipid microdomains have been shown to facilitate spatial separation of proteins, and microdomain association correlates strongly with cell signalling in many biological contexts - offering a route for molecular pre-organisation in a synthetic cell.

The challenge for designing synthetic mimics of lipid microdomains is that lipid-lipid phase separation and the preferential interactions that drive protein recruitment to these domains are not well understood. We aim to take a molecular engineering approach to (i) create lipid microdomains and (ii) use these domains to drive pre-assembly of a transmembrane protein complex. We will build in complexity from the bottom-up, and this work could ultimately lead to new cell-based immunotherapies to fight diseases such as cancer.

In this project, we will explore microdomain formation in synthetic immune cells using biophysical techniques including fluorescence spectroscopy/microscopy, SAXS, ITC, cryo-EM and in in silico model membranes using coarse-grained molecular dynamics computer simulations. We will also explore the partitioning of proteins into lipid microdomains, evaluating the impact of lipid type and protein sequence using a wide range of biochemical and biophysical methods including circular dichroism and NMR spectroscopy. This work will provide a deeper understanding of the "communication" between proteins and membranes that we will use to design a synthetic cell, e.g. a synthetic immune cell.