Award details

Conformational switching for trans-membrane communication

Reference	BB/I007962/1
Principal Investigator / Supervisor	Professor Jonathan Clayden
Co-Investigators / Co-Supervisors	Professor Simon Webb
Institution	The University of Manchester
Department	Chemistry
Funding type	Research
Value (£)	609,437
Status	Completed
Type	Research Grant
Start date	27/06/2011
End date	26/06/2014
Duration	36 months

Abstract

The phospholipid bilayer of the cell membrane is necessarily a chemically impermeable barrier, but one across which information must nonetheless be transmitted. Biology achieves communication through membranes principally either by regulating the flow of ions through pores or by using membrane-spanning molecules (e.g. G-protein coupled receptors, GPCRs). In both cases, a conformational response to ligand binding on the exterior face mediates an interior biochemical event. Attempts to achieve trans-membrane communication have to date relied on constructing 'gated' artificial pores in artificial vesicles or changing the distribution of molecules in the membrane. Trans-membrane signalling mediated by changes in molecular conformation - which is how GPCRs work - has never been realised in a synthetic system, and this is what we now set out to achieve. The questions we propose to answer are these: can remote conformational control, of the type found in allosteric proteins or in GPCR-type signalling, be achieved in artificial systems, using non-biological peptides? Can information about a local change in bonding or structure be usefully propagated along a simple molecule by means of cooperative conformational change? Can that molecule be embedded within an artificial membrane, and how does the bilayer affect the propagation of conformational change? Can information controlling changes in reactivity, ligand affinity, or other detectable features to be relayed between sites now chemically insulated from one another? If it can, science will have at its disposal a new, bioinspired molecular scale mechanism for controlling function and reactivity through a physical and chemical barrier. We will be able to control chemical activity within an artificial cell through interactions on its external surface, without chemical connection between the two. This would constitute a major breakthrough in the fields of biomimetic chemistry, foldamer chemistry and conformational control.

Summary

Cells are surrounded by an impermeable membrane, and one of the challenges living systems face is how to communicate information into and out of the cell through that membrane. The same challenges face scientists seeking to understand cellular behaviour using artificial cells, or vesicles, which can be used as miniature chemical reactors or transporters. Cells solve the problem either by making channels through the membrane which can conduct ions, or by rigging up a type of 'bell-pull' system, in which a tweak at the external surface of the cell leads to a change in shape of a molecule on the internal surface. This latter method has never been realised in a synthetic system, despite suitable molecules with well defined shapes, known as 'foldamers', recently becoming available to chemists. We now plan to put these foldamers to use as communicators ('transducers') of information through an artificial cell membrane. To do this we will have to develop ways of making them and of inputting and reading out information at opposite ends of the foldamer. Firstly, this will be done in solution, and then we will transfer what we discover to the membranes of vesicles. We will develop ways of studying and controlling the shape of molecules in membranes, and then build on this to construct signalling methods which allow the chemistry happening inside the vesicle to be controlled by chemical messages in the outer medium. These artificial analogues of cellular behaviour will greatly simplify the challenges presented to bioscientists wishing to understand the chemical basis of cellular communication in cells. We can also use these vesicles as miniature controllable reactors, or work out ways of making them release their contents at a controlled time or at controlled locations. Furthermore these molecules we plan to build have much in common with the 'peptaibol' class of antibiotics, and our research may give alternative, synthetic antibiotics with controllable function.

Impact Summary

Who will benefit and how? The work we propose investigates a fundamental hypothesis that will advance our understanding of a key biological process. The outcome may not give rise to results which are immediately exploitable commercially. However, the development of functional nano-scale systems in general will underpin many new industries of the 21st century, and this work will contribute to that development. The public will benefit indirectly from the generation of wealth through successful innovation, but also directly where the work contributes to advances in healthcare (eg new antibiotics) or materials. The timescales involved for economic benefits may be measured in decades, though contributions to the antibiotic field could potentially influence advances in this field in a matter or years. It is in the nature of ambitious, innovative science that the impact is impossible to foresee. The creative character of the project, which addresses biological function with artificial structures, will also stimulate related thought and interest, contributing to the quality of scientific discourse in the area. The researchers working on the projects will gain skills which are widely in demand across the pharmaceutical, materials, biomolecular and chemical sectors. The skills include the disciplines of synthesis, physical organic and biophysical chemistry (repeatedly noted as an area of skills shortage by the pharmaceutical industry). They will also have experience of team work and multidisciplinary collaboration, as well as the intellectual benefits of working in a rapidly developing, as yet unestablished, area and all of the opportunities for intellectual creativity (including the development of their own new ideas for future independent research programmes) that such an environment will bring. What will be done to ensure they benefit? The most significant results will be communicated in broad spectrum scientific journals, our aim being at least one paper in Nature orScience. We will also seek to use journals of chemistry with broad readership, primarily Nature Chemistry, Angewandte Chemie and J. Am. Chem. Soc. to give the greatest possible publicity to our work. We have a track record of publication these journals, and we also managed to follow up a previous Nature paper in this field with highlights and news flashes in Chemistry World and Chem. & Eng. News. One of the PI's has also been involved as an interviewed expert on conformation and stereochemistry Radio 4 science programme, and would build on the contacts made at that stage to explore the possibility of further broad publicity of this type. Reports of parts of the work in journals of nanotechnology, peptide chemistry, and surface chemistry will also widen the impact among scientists in related disciplines. Given this work seeks to understand one of the fundamental functions of the cell, aspects are also suitable for reporting in press releases - and hence via popular science dissemination routes such as New Scientist or the science pages of the broadsheet newspapers. This approach has been particularly effective in Manchester recently, with our experience of handling the worldwide publicity attending a recent Nature paper from the School of Chemistry on the chemical prebiotic origin of RNA nucleosides.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	Structural Biology
Research Priority	Synthetic Biology
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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