Periodic Reporting for period 1 - REFOLDAMER (Communication through Polarity-Switchable Foldamers)
Okres sprawozdawczy: 2016-04-04 do 2018-04-03
Nature uses molecules that can change shape to communicate information. In this project we looked to develop artificial methods that could achieve related outcomes more generally, using synthetic compounds. We set out to explore simple chain molecules that can change shape, and to induce them to do this by borrowing some ideas from the structure of DNA. Ultimately, success could lead to new ways of controlling the function of biological systems, ie curing diseases. Our overall objective was to indiuce a single molecule to change shape, and for that change in shape to be transmitted from one end of the molecule to the other. It turned olut that this was a difficult task, and the project made significant discoveries that helped us along the route to this aim, but further work is needed to reach the target. We can conclude from the work so far that selective binding-induced changes in shape are possible, but that communicating that shape change through the molecule is more difficult if the molecule already has a favoured arrangement.
Preliminary work showed that the helical molecules we described as 'Guichard Ureas' had the switchable properties necessary for our studies, so we moved straight on to the challanging aim of inducing them to change shape using binding to DNA-type bases. We designed a switchable binding site based on a pyridine structure and developed low temperature analytical methods to show that although binding-induced local unfolding was possible, relayed shape changes did not occur. We thus moved to a new pyrimidine-based binding site. Binding induced changes in shape were now easier to achieve, and ligands were optimised to favour this but were still not relayed as planned. Modelling in showed that the binbding site needed further careful design, and that the switchable structure needed to be finely balanced between alternative orientations. At the end of the project, the work had reached a stage where a preliminary publication was ready to be prepared, and the fellow is continuing in the lab for a few more months to assemble further data required to complete this and allow the work to be disseminated. The data will be used as a basis to secure further funds in collaboration with computational chemists to optimise the design.
The state of the art at the start of the project was that binding can induce unfolding, and we have shown that this is possible in a number of structures by careful design of ligand and binding site. Relaying the unfolding to induce a longer-range change in shape is now close to success, given the information gained during the project. This is challenging cutting edge science, with the potential to initiate a new area of supramolecular chemistry, with potential long term benefits to health and wellbeing. The project has also trained the fellow in chemical synthesis and studies of binding that will be of benefit to the European Science base in future.