FAUST: Foldamers As Unnatural Signal Transducers
Lead Research Organisation:
University of Manchester
Department Name: Chemistry
Abstract
Research questions
The cell membrane not only defines a cell but also acts as a protective barrier, which means that cells must use specialised transmembrane proteins in their membranes to communicate with the world around them. G-protein-coupled receptors (GPCRs) are one such class of protein. GPCRs transmit a signal when an external messenger molecule (the 'signal') binds to their exterior, which induces conformational changes in the protein that then trigger the release of a message within the cell. The creation of completely artificial molecules that can copy GPCR behaviour and transmit messages across membranes (a distance of several nanometres) would lead to many exciting opportunities. For example, they could provide artificial signalling pathways that 'short-circuit' natural signalling networks, reprograming cells while providing fundamental scientific insights.
Building on our recent work synthesising and studying compounds that mimic aspects of GPCR behaviour (published in Science and Nature Chemistry),1-4 we wish to initiate a new project at the interface of synthetic, supramolecular and biological chemistry; the "catch-and-release" of oxygen by membrane-spanning a-aminoisobutyric acid (Aib) foldamers in membranes.
Approach
This project will start with the chemical synthesis of Aib oligomers that can bind to haemoglobin. These folded oligomers ("foldamers") will be designed to bind a messenger molecule, which causes them to change shape. This shape change will be transmitted along the multi-nanometre length of the foldamer, to perturb haemoglobin conformation and thereby turn oxygen binding on or off. These foldamers will then be used for the "catch-and-release" of oxygen in 'artificial cells' (vesicles) that contain haemoglobin. Finally these foldamers would be inserted into erythrocyte membranes and messenger binding relayed into the cell interior, leading to changed oxygen binding by internal haemoglobin. This unique system would be the first synthetic signal transduction system applied to a natural cell, a huge advance towards truly synthetic biology.
Novel physical sciences content
The project will require the synthesis of large and complex folded molecules that will be embedded in phospholipid bilayers, where their properties will be studied, for example by microscopy and spectroscopy. There will also be the quantitative analysis of the effect of these molecules on the properties of haemoglobin. It will provide the student with extensive training in chemical synthetic methodology, analytical chemistry and supramolecular chemistry. The student will apply different types of physical sciences metrology to protobiological and synthetic biological constructs, leading to a deeper understanding of the natural signaling systems in a cell.
References
[1] R. A. Brown, V. Diemer, S. J. Webb, J. Clayden, Nature Chem. 2013, 5, 853.
[2] M. De Poli, W. Zawodny, O. Quinonero, M. Lorch, S.J. Webb, J. Clayden, Science 2016, 352, 575.
[3] F. G. A. Lister, B. A. F. Le Bailly, S. J. Webb, J. Clayden, Nature Chem. 2017, 9, 420.
[4] Lister, F. G. A.; Eccles, N.; Pike, S. J.; Brown, R. A.; Whitehead, G. F. S.; Raftery, J.; Webb, S. J.; Clayden, J. Chem. Sci. 2018, 9, 6860.
The cell membrane not only defines a cell but also acts as a protective barrier, which means that cells must use specialised transmembrane proteins in their membranes to communicate with the world around them. G-protein-coupled receptors (GPCRs) are one such class of protein. GPCRs transmit a signal when an external messenger molecule (the 'signal') binds to their exterior, which induces conformational changes in the protein that then trigger the release of a message within the cell. The creation of completely artificial molecules that can copy GPCR behaviour and transmit messages across membranes (a distance of several nanometres) would lead to many exciting opportunities. For example, they could provide artificial signalling pathways that 'short-circuit' natural signalling networks, reprograming cells while providing fundamental scientific insights.
Building on our recent work synthesising and studying compounds that mimic aspects of GPCR behaviour (published in Science and Nature Chemistry),1-4 we wish to initiate a new project at the interface of synthetic, supramolecular and biological chemistry; the "catch-and-release" of oxygen by membrane-spanning a-aminoisobutyric acid (Aib) foldamers in membranes.
Approach
This project will start with the chemical synthesis of Aib oligomers that can bind to haemoglobin. These folded oligomers ("foldamers") will be designed to bind a messenger molecule, which causes them to change shape. This shape change will be transmitted along the multi-nanometre length of the foldamer, to perturb haemoglobin conformation and thereby turn oxygen binding on or off. These foldamers will then be used for the "catch-and-release" of oxygen in 'artificial cells' (vesicles) that contain haemoglobin. Finally these foldamers would be inserted into erythrocyte membranes and messenger binding relayed into the cell interior, leading to changed oxygen binding by internal haemoglobin. This unique system would be the first synthetic signal transduction system applied to a natural cell, a huge advance towards truly synthetic biology.
Novel physical sciences content
The project will require the synthesis of large and complex folded molecules that will be embedded in phospholipid bilayers, where their properties will be studied, for example by microscopy and spectroscopy. There will also be the quantitative analysis of the effect of these molecules on the properties of haemoglobin. It will provide the student with extensive training in chemical synthetic methodology, analytical chemistry and supramolecular chemistry. The student will apply different types of physical sciences metrology to protobiological and synthetic biological constructs, leading to a deeper understanding of the natural signaling systems in a cell.
References
[1] R. A. Brown, V. Diemer, S. J. Webb, J. Clayden, Nature Chem. 2013, 5, 853.
[2] M. De Poli, W. Zawodny, O. Quinonero, M. Lorch, S.J. Webb, J. Clayden, Science 2016, 352, 575.
[3] F. G. A. Lister, B. A. F. Le Bailly, S. J. Webb, J. Clayden, Nature Chem. 2017, 9, 420.
[4] Lister, F. G. A.; Eccles, N.; Pike, S. J.; Brown, R. A.; Whitehead, G. F. S.; Raftery, J.; Webb, S. J.; Clayden, J. Chem. Sci. 2018, 9, 6860.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/R513131/1 | 01/10/2018 | 30/09/2023 | |||
| 2291569 | Studentship | EP/R513131/1 | 01/10/2019 | 30/06/2023 | Rhodri Evans |