Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

There are a number of experimental methods that people use to obtain answers to specific biological questions. In most cases, however, one single technique cannot provide a complete answer. Because of this, it is common practice to use more than one experimental technique and then to combine all the information together to build up a detailed picture of what is happening. One very useful techinque that is under-utilised in the UK is electron paramagnetic resonance (EPR). This method is capable of detecting free (unpaired) electrons. This is useful because the unpaired electrons act as 'spies' on the molecule and can provide information on local environment. This means that EPR can be used to report on biological (free) radicals, on (paramagnetic) metal centres in biological systems and on protein dynamics. At Leicester, we do not have access to an EPR facility that is suitable for biological work. This slows our work down because it means that we cannot obtain some of the information that we need as fast as we would like to. The current proposal seeks funding to address this problem.

Proteins are dynamic molecules. Motions within a protein molecule can be localised (e.g. bond vibrations, backbone and side chain motions) occuring on relatively fast timescales, or large scale motions (domain motions, conformational changes and slow breathing modes) that typically occur on the millisecond to second timescale. Localised fast motions can influence the chemistry in enzyme active sites; larger scale motions bring active sites together, or facilitate long range communication, for example in the transfer of electrons over large distances in redox enzymes, information transfer through signalling cascades or the folding of protein molecules. These large scale motions give rise to the concept of energy landscapes - that is the free energy surface that accommodates all conformations of the protein macromolecule that are populated. The distribution of conformational states across this landscape can be perturbed, for example by ligand or drug binding, natural variation in sequence (polymorphisms) or partner protein binding. Our knowledge of the spatial distribution and temporal exploration of these landscapes is at best limited, attributed in the main to the lack of general structural and biophysical tools to capture this information. The three dimensional structures of 'rigid' protein modules are readily accessed using conventional approaches (crystallography, NMR spectroscopy). How multiple modules communicate in complex protein systems however is not accessible using these techniques. In this application we aim to develop robust experimental methods using state-of-the-art spectroscopic, kinetic and computational methods that enable investigators to study the spatial and temporal properties of landscapes and their remodelling by small molecule/protein binding. We aim to develop these methods using mammalian nitric oxide synthases, redox enzymes that are constructed from multiple functional domain the chemistry of which is coupled to major dynamical excursions during the course of the enzyme catalysed reaction. We aim to define the structures of multiple conformational states across the landscape, define the timeconstants for their interconversion and assess the functional importance of these structural transitions in the catalytic cycle of the enzyme. By providing atomic level spatial and time resolved information on the functional dynamics in nitric oxide synthase enzymes we envisage that new opportunities will accrue to develop selective inhibitors that interfere with dynamical processes linked to function. This will reinvigorate the search for isoform specific inhibitors of these enzymes, and also provide general tools for similar analysis of other dynamic systems from which function and therapeutic intervention can be studied.

Our vision is to create a distributed CDT that unites the strands of magnetic resonance (MR) technology funded under the EPSRC Basic Technology (BT) Programme that accounted for more than 10% of the funding in this programme. We will create a world-leading combination of expertise, infrastructure resource and training. Furthermore this vision seeks to capitalise on the BT investment by developing MR technology to have real and lasting impact on UK science and industry. The UK has an outstanding and continuing record of contributions and advances to many aspects of MR research and technology. UK-based companies (e.g. Oxford Instruments, Magnex (now part of Agilent), Cryogenics, Bruker UK, Thomas Keating) using highly trained staff with higher degrees (e.g. MSc, PhD) have pioneered world-leading MR technology, much of it emerging from UK universities. The letters from our industrial partners are absolutely clear about the need for an increased supply of MR researchers trained to PhD level with a broad perspective of the field to maintain the UK's position at the forefront of the development of MR technology. MR methods are firmly established as a primary analytical tool in chemistry, are increasingly influential for characterisation in materials science and have revolutionised medical imaging. Despite the great success of MR there is huge demand to push the boundaries through increasing the sensitivity, resolution (spectral and spatial) and speed of the technique. The technologies involved include fast, high power and versatile electronics, signal detection and processing, high frequency/power sources, cryogenics, micromechanics, sample environments and pulse sequences. These drivers, the range of technologies involved and strong, integrated industrial involvement make the field an ideal research training ground for our PhDs and ensure wider BT impact. The CDT will provide impetus for further cross-collaboration in the UK MR community, with the projects jointly supervised across partners. Our vision centrally fits this CDT call by exposing students to multiple, but synergistic BT concepts around MR. Although the physical principles of the different branches of MR, i.e. nuclear (NMR), electron (EPR) and imaging (MRI), are fundamentally related, conventional 'isolated' PhDs associated with one specific MR topic often miss the connection and broader picture of the field. This CDT will bring new dimensions to the training of a cohort of UK PhD students in MR including acquiring the background skills for creative exploitation of their research. PhD projects centred on developing MR technology will have multidisciplinary impacts Page 3 of 9 Date printed: 20/01/2011 11:21:23 EP/J00121X/1 Date saved: 20/01/2011 10:45:13 through extending the range of application of MR techniques. The MR instrument market (certainly worth many hundreds of millions of pounds globally) continues to show strong growth as evidenced by the annual reports of the leading companies and by their projected forecasts of rapid expansion. Hence the already identified need along with the potential growth amply demonstrate the demand for trained people in this area. There is a strong fit to national needs in priorities aligned to RCUK, industry and more broadly. Increasingly there are national concerns about critical mass and improved sustainability through shared services/infrastructure. The demand for very expensive state of the art equipment in MR to compete internationally will require more coordination and joint planning between the leading groups and this CDT can play a central role in this. Specific areas of MR technology where training will be provided and also further developed through the research projects of the students are: (i) MR Pulse Sequence Technology (ii) Cryogenic Magnetic Resonance (iii) Advancing pulsed Electron Paramagnetic Resonance (iv) Beyond conventional Magnetic Resonance Imaging (v) Dynamic Nuclear Polarisation enhanced NMR