O'Mara Group Honours Project

Membrane lipid composition influences the localisation of membrane proteins and regulates their activity. The hundreds of chemically distinct lipids within cell membranes phase-separate to form microdomains that impact the localisation and interactions of membrane proteins. The composition of the cell membrane is tightly controlled in normal cellular function. There is now considerable evidence that altered cell homeostasis, ranging from inflammatory processes to cancer, cause alterations in metabolic pathways which impact membrane lipid distributions, cell biophysical properties and membrane protein function. This may have downstream impacts on the uptake and efficacy of a range of pharmaceuticals used to treat dysfunction. This project will examine how changes in lipid membrane composition in cancer and other disease states impacts drug uptake. This knowledge will provide a means specifically target a given cell type through the design of cell-specific carriers systems for drug delivery.

Lipid delivery systems have a wide range of applications, from cosmetics to the food industry to drug and vaccine delivery, and involve strategies varying from encapsulated liposomes, PEGylation, and simplified emulsions. Each employs a different delivery strategy, ranging from cell membrane fusion to endosomal uptake, allowing tuning of the system to optimise uptake. To date, very little is known regarding how the membrane microenvironment influences the membrane partitioning of a lipid delivery system or their cargo bioactive molecules; or how this facilitates delivery to the membrane protein target. This project will focus on the computational development of lipid delivery systems that will selectively partition into phase-separated complex membrane systems by examining the effect of factors such as the surface charge and lipid ordering on the fusion and partitioning of lipid delivery systems.

The development of effective therapeutics that target chronic pain in neurological diseases would significantly improve the quality of life for millions of people living with chronic pain. The glycinergic neuronal transport proteins are a promising target for the treatment of chronic pain. In neurons and other cells, the membrane lipid composition influences the localisation of membrane proteins and regulates their activity. The hundreds of chemically distinct lipids within cell membranes phase-separate to form microdomains that impact the localisation and interactions of membrane proteins. Oxidative stress is an early hallmark of inflammation and disease that causes chemical modifications to membrane lipids, proteins, and other biomolecules. This impacts their function and influences their biophysical properties. This project will examine the effect of oxysterols and neurosteroids on the inhibition of glycernergic synaptic membrane proteins for the development of targeted therapeutics for the treatment of chronic pain in specific disease states. This is a computational project. The direction of the project can be tailored to the interests of the student.

Bacterial multidrug efflux pumps are the bacteria’s first line of defence against the action of antimicrobials. However, very little is currently known about the function and substrate range of these efflux pumps. This project will examine different multidrug efflux pumps to uncover the structural basis of substrate specificity and transport. It will examine the impact of bacterial membrane modifications on bacterial multidrug efflux pump function, and how peptide- and/or polymer-based antimicrobials inhibit multidrug efflux pumps and disrupt membrane integrity. Other avenues of investigation include characterising the effect of lipid modifications in antimicrobial resistance, and computational drug design of lead new candidates for antimicrobial design. This project uses a range of computational techniques, primarily multiscale molecular dynamics simulations.