A Coordinated Infrastructure for NMR for the Physical and Life Sciences: Upgrade to the Ultra-high Field 950 MHz Spectrometer at Oxford

Uncovering the dynamics and three-dimensional arrangements of the millions of biological macromolecules in a cell remains a formidable task. Yet we need to know how these molecules assemble and interact if we are to understand the emergent property called life. Although large-scale efforts, such as the human genome project, have provided us with the sets of components that make up living organisms, we are still some way from comprehending how these components come together to form the molecular machines that carry out all the basic biological functions.

Similar to engineers, we need to "see" the shape of components to understand their role and place in functional assemblies. Nuclear Magnetic Resonance (NMR) spectroscopy is currently the only method that can provide us with detailed views of biological components under conditions similar to those that occur in living organisms, or even in the living cell itself. As such, NMR studies complement other structural methods which rely on creating immobilised assemblies, such as crystallography and electron microscopy. As well as structural information NMR gives unique information about the dynamic behavior of these components over time, which can be related to events such as chemical catalysis, and insight about associations occurring between components that complements information from other biophysical methods.

NMR instrumentation consists of large, powerful, and very expensive magnets, and electronics that transmit and record experimental signals. In this proposal, the University of Oxford requests support from the UK Research Councils to upgrade our existing ultra-high field 950 MHz NMR system, which features the most powerful magnet in the UK, with the latest generation of high-sensitivity electronics for signal detection. This so-called "cryoprobe" upgrade will boost the measured signal by a factor of ~2-4 enhancing the quality of experimental data collected and enabling more challenging molecular systems to be studied. Coupled to an automation accessory that will allow round-the-clock use of the upgraded NMR system, our proposal represents the most cost-effective and efficient means of increasing cutting-edge NMR capacity and capability in the UK (~£535K for the proposed upgrade versus ~£5M for a similar new system).

Once upgraded, 50% of the time on the 950 MHz NMR system will be made available to external users from other UK academic institutions and from industry. In particular, we aim to assist users from the south of England and Wales, for which Oxford is well placed to serve as an easily accessible regional NMR hub.

We expect the proposed equipment upgrade to have societal and economic impact through two distinct pathways: direct relevance to life sciences, and the training of researchers.

NMR is an established analytical method for characterising the properties of biological macromolecules. Contrary to X-ray crystallography, however, solution-state NMR can provide information under near physiological conditions, in membrane-mimicking environments or even in living cells. Thus, NMR-derived information is uniquely important not just for structural biologists but more broadly for researchers interested in mechanistic aspects of life. We believe that this wide group, which nowadays includes cell biologists, biochemists, chemists and physicists, will directly benefit from the improved data quality afforded by the upgraded instrumentation.

Scientists based in industry will also benefit from the upgraded NMR spectrometer at Oxford. NMR is widely used in the UK biotechnology and pharmaceutical industries for screening libraries of potential drug molecules and for characterisation of the structure and dynamics of 'druggable' target proteins. Because of the high cost of investment, pharma companies generally do not have in-house ultra-high field NMR systems that are required for studies of some of the most challenging systems. We are aware of demand for access to ultra-high field NMR time from pharma companies including UCB Celltech and Vernalis and will welcome such industrial users on our upgraded 950 MHz system.

Thus, the upgraded 950 MHz spectrometer at Oxford will provide novel opportunities for UK researchers working in both academia and industry to describe challenging biological systems and thereby contribute to our understanding of molecular mechanisms underpinning health and disease.

In addition to basic research considerations, the availability of cutting edge tools directly impacts on the education and training of students and staff in the UK. The Oxford Biochemistry solution-state NMR facility provides opportunities for training and experimentation for undergraduate and graduate students, as well as postdoctoral and early career researchers. We expect that researchers using the upgraded system will gain insights into novel, powerful NMR methods, and they will then be able to re-use this experience in other facilities, whether in academia or industry. Moreover, the structural biology groups using the 950 MHz spectrometer have established interdisciplinary collaborations with molecular and cell biologists, thereby facilitating two-way transfer of ideas and opportunities between NMR researchers and those from collaborating laboratories.