Conformational Design of Cyclic Peptides

This project will develop and test methods for designing cyclic peptides at the conformational level. Cyclic peptides can have high biological activity, which is due to their 3D structure. However, predicting this structure is difficult due to the conformational constraints imposed by cyclisation, and the many degrees of freedom still available to the molecule. This project will address this through a combined computational and experimental programme. In the first instance, cyclic peptides with higher (e.g. C3 or C4) symmetry will be addressed. Information on local peptide conformation will be gleaned from natural protein structures and used to generate models, which will support the identification of targets for chemical synthesis and structural analysis. Conformations in solution will be identified via NMR experiments and other biophysical methods, including circular dichroism spectroscopy. Experimental information will be fed back to improve the model-building protocols. This workflow will give rise to new methods that will allow the design of cyclic peptides at the conformational level. These methods will be applied to challenges in supramolecular chemistry, for example in the design of new highly-specific guest-binding macrocycles, and in chemical biology, for example in the design of cyclic peptides that are capable of interfering with protein-protein interactions. The core work here will be in keeping with several key EPSRC subject areas, most notably the Chemical Biology theme.