The µ-opioid receptor (MOR) is a key player in pain modulation, addiction, and the pharmacological effects of opioid drugs, such as morphine and fentanyl . The membrane plays a crucial role in modulating the activity of many membrane proteins, including G protein-coupled receptors (GPCRs) such as MOR. In particular, membrane features such as curvature and lipid composition, which vary based on membrane type – e.g. presynaptic vs. postsynaptic membranes, are thought to influence receptor function. This location-specific activity is poorly understood but is likely to impact the mechanism of opioid action  and contribute to the design of improved opioid drugs. This project will investigate the effect of membrane behaviour and cellular localisation on MOR pharmacology.
The project will be interdisciplinary: the primary research will be computational, but the student will be able to learn and implement a variety of wet lab techniques during visits to co-supervisor labs. The main objectives will be to characterise: 1. the influence of membrane lipid composition on MOR: lipid composition varies between membranes. The student will use coarse-grained molecular dynamics (MD)  to investigate the interactions of different lipids with MOR, and apply free energy calculations to determine the impact of lipid composition on MOR-opioid binding affinity . 2. the impact of membrane curvature on MOR: membrane curvature can influence the organisation and activity of membrane proteins.
The student will use MD to see how membrane curvature affects MOR in terms of dynamics, dimerization, and interaction with opioids and other binding partners. 3. the pharmacology of MOR in lipid raft microdomains: Cholesterol-rich membrane microdomains impact the function of several GPCRs, including MOR. Using state-of-the-art computational methods, such as enhanced sampling, the student will explore how these domains affect aspects of MOR function, including the binding of opioids.
This project will employ a range of cutting-edge computational methods, which have emerged as powerful tools in the modelling of biomolecular structures and dynamics, including protein-drug interactions. There will also be opportunity to learn programming and Data Science skills using Python. The computational findings will be validated and given a broader physiological context using functional data generated in the labs of the co-supervisors, all of whom are experts in MOR. This will involve introducing mutations that change the lipid-binding, curvature-seeking, or raft-associating properties of MOR, or genetically/chemically changing
ABOUT THE GW4 BIOMED2 DOCTORAL TRAINING PARTNERSHIP
The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP has already awarded over 90 studentships across 6 cohorts in its first phase, along with 38 students over 2 cohorts in its second phase.
HOW TO APPLY
Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’ on GW4 BioMed MRC DTP - GW4 BioMed MRC DTP
Please complete the online application form linked from the DTP’s website by 5.00pm on Wednesday, 1st November 2023. If you are shortlisted for interview, you will be notified from Tuesday 19th December 2023. Interviews will be held virtually on 24th and 25th January 2024. Studentships will start on 1st October 2024.
If successful, you will also need to make an application for an 'offer to study' at University of Bristol - Physiology, Pharmacology and Neuroscience | Study at Bristol | University of Bristol
For enquiries relating to the DTP programme or funding, please contact [Email Address Removed]
Please contact the project supervisor for project-related queries.