PhD Studentship: Sending A Message Down A Golden Thread

Application deadline: All year round
Research theme: Organic and supramolecular chemistry

How many positions: 1 

This 3.5 years PhD project is fully funded; tuition fees will be paid and you will receive a tax free stipend (depending on circumstance) set at the UKRI rate (£19,237 for 2024/25). The start date is October 2025. This project is for home students only. 

Background: Transmembrane receptors in cell membranes, like G-protein coupled receptors (GPCRs), relay chemical messages into cells in a process called “signal transduction”. With approx. 35% of approved drugs targeting GPCRs,[1] understanding how these important proteins function is a key goal for biomimetic chemistry. Furthermore, engineering synthetic molecules that can mimic GPCRs could make cells externally controllable using unnatural stimuli; “short-circuiting” natural signalling pathways.

Aims: This multidisciplinary PhD project, which links organic chemistry to biology, will develop synthetic molecules able to transmit signals across phospholipid bilayers.[2] These signals will switch gold(I)-catalysed reactions on or off. The synthetic molecules (receptors) will comprise a gold(I) complex attached to a [2]pseudorotaxane core, a structural motif that has a molecular “thread” passing through a molecular “ring”. After insertion of the [2]pseudorotaxane receptors into bilayer membranes, enzymatic modification of the exterior part of each [2]pseudorotaxane receptor will move the thread through the ring. This motion will in turn either activate or deactivate the gold(I) catalyst, which is located on the other side of the membrane.

Approach: The project will build on ongoing work. It will start with the chemical synthesis of catalytically active [2]pseudorotaxanes and control compounds. The ability of supramolecular interactions and catalysis to initiate motion in prototype [2]pseudorotaxane systems will be quantified in organic solvents, with this knowledge used to understand analogous behaviour in cell mimics (vesicles). Initially the production of fluorescent products in solution and inside vesicles will be measured. Then the best performing systems will be studied in the membranes of living cells, with external stimuli switching on/off the catalytic production of messenger molecules.

Outcomes: A key outcome would be the first example in cells of molecular thread motion through a molecular ring. Furthermore, should this movement alter cell behaviour, cells will have been made externally controllable using unnatural chemical stimuli. Receiving, communicating, and transforming molecular information into a catalytic output will be an underpinning technology for molecular robotics.

The candidate: This project would suit an applicant with core knowledge/skills in chemical synthesis and supramolecular chemistry. An understanding of how to analyse catalytic reactions is desirable. An interest in biological systems will be needed, although no prior experience of cell culture techniques is required.

[1] Sriram et al, Mol. Pharmacol. 2018, 93, 251. [2] (a) Editorial in Nature Chem. 2017, 9, 403. (b) Lister, et al. Nature Chem. 2017, 9, 420. 

Applicants should have, or expect to achieve, at least a 2.1 honours degree or a master’s (or international equivalent) in a relevant science or engineering related discipline.

Please contact Prof. Webb (S.Webb@manchester.ac.uk) before you apply. Please include details of your current level of study, academic background and any relevant experience and include a paragraph about your motivation to study this PhD project.

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