A globally unique 19F, 13C, 15N NMR system to enable frontier bioscience

We use a technique called Nuclear Magnetic Resonance spectroscopy (NMR) to study the structure of biomolecules that form the intricate machinery of cells and organisms. Their structure determines how they work and interact with each other and forms the basis of considerable human effort in understanding cutting edge bioscience.

We are proposing to purchase the world's first TXO-HF NMR cryogenic probe technology and use it to make ground-breaking discoveries in areas such as neurodegenerative conditions like Parkinson's disease, design the structure of new biomolecules, or the production of antiviral, antibiotic and antifungal compounds. We can also use this new NMR data to design or repurpose drugs to make them more potent and even look at what happens to next generation drugs when your body tries to metabolise them. We have already identified >£30m of funded research programs, national collaborations and doctoral training programs that this instrument will underpin from day one, and we are working with a range of national networks who will allow us to increase this substantially over the lifetime of the NMR instrument.

The new probe will enable this research because NMR shares the same basic ideas as the whole-body MRI scanners that are found in hospitals. However when studying molecules in bioscience, it is difficult to get enough sample to detect with our NMR spectrometer and the 'standard' atomic nucleus that MRI studies (the proton), tends to be so abundant that it gives very 'noisy' spectra with too many signals for us to be able to interpret.

The solution to these problems is to use an NMR 'cryoprobe' that has very sensitive detection and is optimised to look at other types of atomic nuclei that tend to give more spread-out signals. Some NMR systems have started to use carbon and nitrogen nuclei, but what makes this TXO-HF system we are going to install especially powerful is that it can also use a further nucleus, fluorine, that is uniquely powerful as a probe because it is rare in most natural systems. This means we can use cutting-edge biosynthetic techniques to introduce fluorine into the molecules we study and then follow it's behaviour without all of the background noise that is found with proton-based NMR and thus study some very difficult problems in biology.

There are many more important and complex scientific questions to answer with this new equipment and to do this we have teamed up with many partner universities, national NMR network programs and biopharmaceutical companies. By bringing all of these different groups together we are ensuring we maximise the number of people and have a broad expertise that can be applied to the scientific challenges we face. As the national picture of how universities work together evolves, sharing (expensive!) unique and sophisticated equipment like this becomes ever more important. Therefore part of what we are seeking to do with this equipment is use it as an exemplar to encourage collaboration and training for our skilled research technical professionals who run these instruments, as well as to inspire the students who themselves will go on to be the bioscience researchers and NMR spectroscopists of the future. To do this we have engaged with a dedicated team who champion this idea and through which we hope to make the equipment even more impactful and sustainable.

Ultrahigh-field magnets (1GHz) satisfy some of the escalating demands of biological NMR but do not circumvent many of the underlying problems with traditional 1H-detection used by most NMR technologies. Instead, the key to addressing many of these challenges is the observation of 13C, 15N AND 19F nuclei. Recently developed direct observe (TXO) cryoprobes have partially addressed this with a leap in 13C/15N sensitivity to enable otherwise impractical NMR techniques. However, the increasingly key role of 19F in bioactive molecules requires a new approach.

We will install the world's first cryoprobe which introduces 19F to TXO technology. 19F is more NMR-sensitive than 13C/15N and provides better spectroscopic resolution due to a low natural abundance in biological systems. Combined into one probe, the next generation 'TXO-HF' will enable the UK to tackle bioscience challenges of the future.

The system will be integrated with the collaborative, cross-disciplinary environment of the University of Bristol NMR Facility. The investigators, who lead this facility, are widely recognised as pioneers in providing open access to NMR technology and they serve >200 multi-disciplinary researchers regionally and nationally studying a wide range of scientific problems across BBSRC's remit. We have already identified ~20 collaborators wishing to use the TXO-HF on existing scientific challenges, underpinning >£30M of funded research from day one. We are active participants in several national networks of NMR scientists and they would engage with us to maximise the impact of the TXO-HF to the widest range of UK science.

Such high-end instrumentation is critically reliant on the expertise of the Research Technical Professionals (RTPs) who operate it and train its users. Consequently, this proposal includes substantial training and outreach opportunities for RTPs and research students across GW4 and UK landscape to ensure that future experts in NMR are developed and supported.