A Double Dose - Steroid Dimers for Synthetic Signal Transduction

This project aims to develop an alternative form of transmembrane signalling that utilises a new molecular tool: rigid-rod molecular rotors. We will create a lever-type system with restricted movement. This project will capitalise on recent work from the PI's group that has used conformational change to open a path towards artificial signal transduction, providing light-switchable mimics of rhodopsin and other G-protein coupled receptors.

We are familiar with the tools around us in the macroscopic world, from complex machines (e.g. computers) to simple components (e.g. rotors). There also exists a world of biological molecular machines (typically proteins) that operate in cells and mediate many of life's fundamental processes. One of these processes is the transmission of information and molecules across the cell membrane, a protective barrier that is several nanometres thick. Specialised transmembrane proteins, such as G-protein coupled receptors, recognise external chemical messengers ('signals') and turn these into chemical information ('reports') inside the cell, in a process that usually involve a change in protein shape (conformation).

This project aims to use multi-nanometre long rigid-rod molecular rotors to develop a new way of transmitting information across membranes. These entirely artificial molecular rotors will be designed to change shape after binding to an external chemical 'signal'. This shape change will transmit the information in the signal across both synthetic and natural membranes. This project will use synthetic supramolecular chemistry to open a pathway towards artificial signal transduction.

The project will employ synthetic organic chemistry to create a family of dimers, each of which will bear a different 'reporting' group, such as a fluorescent dye, catalyst, and protein/enzyme inhibitor. After first characterising the behaviour of these compounds in organic solvents, they will then be studied in the membranes of simple cell mimics (phospholipid vesicles). As well as developing skills in synthetic and supramolecular chemistry, the project provides the opportunity to work in chemical biology and biological chemistry. The student will learn cell culture techniques, as the last stage involves studying the behaviour of these molecular rotors in mammalian cell membranes. If successful, this system would be a truly synthetic biology platform that will lead to many exciting opportunities, for example providing artificial signalling networks that reprogram cells and produce fundamental scientific insights.