A high field NMR facility at Dundee for structural and interaction studies.

All matter consists of atoms and at the nucleus of every atom are protons and neutrons. Nuclei that contain an odd number of protons or neutrons are magnetic. Nuclear Magnetic Resonance (NMR) spectroscopy uses very powerful magnetic fields and pulses of radio waves to exploit the magnetic properties of 'odd-numbered nuclei' such as 1H (hydrogen atom or proton), 15N (nitrogen), 13C (carbon), 19F (fluorine) and 31P (phosphorus). Using this technique it is possible for scientists to identify almost every different atom in a protein, nucleic acid, or small drug molecule. This can be very useful, for example, in building up a picture of the 3-dimensional structure of one of these molecules. At Dundee University NMR spectroscopy has been used to determine the structures of nucleic acids and some proteins. The possible uses for NMR spectroscopy are much more varied, however. It is possible to determine the overall size of a protein or complex of proteins, for example, and it is possible to detect which particular atoms of a protein or other molecule undergo a change in local environment when another protein or molecule interacts with it. When proteins 'talk' to each other in the cell they very often physically interact, and NMR can therefore help scientists identify interacting partners. NMR has proven to be immensely useful in drug discovery by identifying small molecules that bind to target 'receptors' of medical interest. In this application nine scientists from the College of Life Sciences outline their ideas for using a new NMR instrument to enhance their research. There are four broad topics under investigation: 1. Bacterial protein transport 2. Nucleic acid structure and folding 3. NMR in drug development 4. Protein modification and its role in gene regulation All of these already well-funded and world-class research projects propose to use NMR spectroscopy to determine structures and/or to assess interactions between molecules. The need for an upgraded NMR spectrometer at Dundee is very great. In recent years the College has expanded its structural biology, molecular microbiology, and drug discovery programs. The machine with the largest magnet in Dundee ('11.744 Tesla' or '500 MHz' spectrometer) is 18 years old and requires upgrading. The College of Life Sciences has commissioned a central suite of smaller NMR and Magnetic Resonance Imaging (MRI) spectrometers within the new Sir James Black Centre. It is proposed here to upgrade the existing 500 MHz spectrometer (at a fraction of the cost of buying a brand new instrument) and to house it in the central 'Nuclear Magnetic Resonance Spectroscopy and Imaging Facility'. The quality of the researchers and research outlined in this proposal, coupled with the versatility, sensitivity, and cost-effectiveness of the upgraded spectrometer requested, will promote increased local, national and international collaborations between scientists, attract a constant stream of new research funding, result in high quality research publications, novel structures and pharmaceuticals, as well as teaching and training future generations of NMR experts.

High resolution, heteronuclear, NMR spectroscopy is a well-established and powerful tool in the determination of 3D protein, nucleic acid and small molecule structures. NMR spectroscopy is also a sophisticated biophysical tool in its own right and is perfectly suited to studies of protein-protein, protein-nucleic acid, and other protein-ligand interations. Indeed, NMR spectroscopy has become a major component in the modern drug discovery process providing key information during pre-clinical drug development. Research programs in the College touch on all of these areas. The recent investment of the College in structural biology, molecular microbiology, and drug discovery has seen resurgence in the need for a high field NMR spectrometer . Researchers working in fields as diverse as bacterial protein transport, nucleic acid structure and folding, drug discovery, and protein modification, have joined-forces here to highlight their desire to maintain a local high field NMR facility at Dundee. The existing 500 MHz spectrometer is unshielded (therefore space and cost inefficient) and approaching 18 years old. In this proposal this spectrometer will be moved to the 'Nuclear Magnetic Resonance Spectroscopy and Imaging Facility' in the Sir James Black Centre and upgraded to state-of the-art specifications including a new shielded 11.744 Tesla magnet, serviced cryoprobe, autosampler system, and the latest software. This modernisation and rationalisation package will provide a heavily-used, sensitive, and versatile instrument at the fraction of the cost of a brand new machine. Given the quality of the research outlined in this proposal it is anticipated that preliminary data generated from the 'new' 500MHz spectrometer within the centralized NMR facility will generate a constant stream of new research funding, high quality research publications, and novel structures and pharmaceuticals, as well as contributing to training future generations of NMR spectroscopists.