Aston Institute for Membrane Excellence
This studentship is supported by the Aston Institute for Membrane Excellence. AIME is a unique, interdisciplinary, intersectoral research and training hub for translational membrane science. AIME is a globally unique, cross-disciplinary institute to develop novel membranes for use in applications as varied as drug discovery and water purification. The team behind AIME believes that the full potential of membranes will only be realised by a research team spanning biology, physics and chemistry that can investigate membranes holistically. No other institute has the platform, potential or promise for major breakthroughs in this area. The vision is for AIME to become a ‘one-stop shop’ for interdisciplinary, translational membrane research through access to its facilities and expertise, ideally located in the heart of the UK.
Details of the Project
Background
Membrane proteins (MPs) are vital for the transport of molecules across cell membranes and intracellular communication and are often key targets for drug discovery. Under natural conditions, MPs exist within compositionally complex lipid membranes which mutually influence each other. For detailed structural and functional studies, isolation and purification of MPs needs to be performed whilst maintaining their stability and activity. When compared to the isolation and purification of soluble proteins, this is a significantly more laborious task. Traditionally, protein extraction has been performed using detergents. However, they tend to strip away the native lipid membranes and often lead to protein instability. Therefore, efforts have been focused on new methodologies to improve the solubilization and stabilization of MPs.
One approach that has seen a major uptake in the last decade, is the use of amphiphilic copolymers to solubilize MPs directly in their natural environment in the form of polymer-bound lipoprotein nanoparticles.1 Amphiphilic copolymers, in contrast to harsher detergents, preserve the native lipid environment of MPs, affect their structure to a lesser degree, and allow direct extraction of MPs from biological membranes avoiding the use of detergents at preliminary steps. The approach is not without limitations, the most widely used copolymer, styrene-maleic acid (SMA), is sensitive to low pH & divalent cations, which hinders the formation of the lipoprotein nanoparticles. Furthermore, free SMA can interfere with protein binding or inhibit activity and may restrict the full dynamic function of proteins. Therefore, new amphiphilic copolymers need to be designed to overcome the limitations of SMA-based polymers.
The expansive chemical space available to polymer chemists makes it hard to know what areas to start looking at. Automation has emerged as a powerful tool for high-throughput polymer synthesis and has enabled faster and more efficient polymer discovery. Furthermore, by combining automation with machine learning algorithms a closed loop can be created allowing the platform to act autonomously without the need for human intervention.2
Aims and Methods
This project looks to leverage the power of automation to create libraries of new polymer candidates as alternatives to SMA polymers for membrane protein extraction. The project aims to:
· Develop automated platforms for the synthesis of amphiphilic copolymers.
· Create and automate assays to assess the viability of new polymer candidates for membrane protein extraction.
· Incorporate machine learning algorithms to allow for autonomous design of new polymers for membrane protein extraction.
For more information and to apply visit https://www.findaphd.com/phds/project/accelerating-the-discovery-of-the-next-generation-of-polymers-for-membrane-protein-extraction/?p176690