Enabling new characterisation methods for dynamic systems through the upgrade of 700 MHz solution NMR spectrometer

The high field 700 MHz solution NMR spectrometer at the University of Warwick was installed during 2004-2005. Since then it has supported large number of research projects mainly funded by the BBSRC and other UKRI councils, led to numerous high-impact interdisciplinary publications in journals such as Nature, Nature Chemistry and Nature Chemical Biology. It has also played a pivotal role in training up the next generation of NMR specialists, many of our research students/PDRAs have benefited enormously from accessing to this instrument. The instrument is central to biomolecular solution NMR research activities, across departments within the University of Warwick via multidisciplinary collaborative networks, as well as supporting high-profile collaborations outside Warwick. However, after more than a decade of heavily usage, it is now >5 years beyond its end-of-life cycle, the Avance II console and the old TCI cryoprobe are completely obsolete, resulting in frequent malfunctions, extended downtime and limited capabilities. More importantly, since the spectrometer's installation, huge advances have been made both in the console design and cryoprobe technology, which enable a wide range of new powerful techniques and are not possible with the old-generation of instrumentation.

In this proposal, we request funds to renew the 700 MHz solution NMR system by upgrading the aging console to Avance NEO and purchasing new cryoprobes, TXO and TCI, which will expand our NMR capacity and enable cutting-edge capabilities in biological NMR spectroscopy, to support large number of both established and early-career research staff (>20 PIs and their research groups) involved in a wide range of internationally leading research. The proposed upgrade is of utmost urgency to avoid negatively impacting on a well established and very successful field of research at Warwick. The new TCI probe will deliver substantial improvements in sensitivity for samples dissolved in high ionic strength physiological solutions and supporting work from small molecule, bioactive natural products discovery to proteins. It will also provide new capabilities for fluorine spectroscopy and related state-of-the-art experiments for characterising interactions, conformational dynamics and structures of biomolecular systems (e.g. protein-glycan systems and large protein complexes). The addition of a TXO probe will additionally bring new cutting-edge capabilities for advanced large and dynamic protein-based work, which will fortify our internationally leading position in field such as genome guided bioactive natural product discovery and integrated structural biology of biosynthetic enzymes.

Both local and national NMR communities in the UK can also benefit from this upgrade, we have co-ordinated our application with colleagues in the Midland to ensure that newly gained capabilities are complementary with existing facilities in the region. We also proposed to offer up to 15% of the instrument time to the UK NMR communities through a transparent peer-review process and access mechanism integrated with the UKRI funded ConnectNMR network.

The Warwick Chemistry 700 MHz solution NMR spectrometer was installed during 2004-2005, with Avance II console and TCI cryoprobe, one of the best in the UK at the time. The instrument has since supported large number of research projects, with many of them funded by the BBSRC. Through our open access management system, hundreds of students have received advanced NMR training on this instrument. However, the instrument is now more than 17 years old, the console and the cryoprobe are regarded as completely obsolete by EPSRC's definition in the 2017 report on UK NMR infrastructure. Therefore, upgrading the 700 system is urgently needed.
To capitalise on the emerging research technology, we propose to upgrade the 700 system with state-of-the-art console and TXO and TCI cryoprobes. This will bring a step change in our capabilities for detailed investigations of large protein complexes, intrinsically disordered proteins and interactions of biomolecular systems. There is currently no versatile 700 MHz solution NMR spectrometer within the Midlands: this will maximise the UKRI large investment into the hub-and-spokes model for national NMR infrastructure.
The upgrade will bring a new life (at least 10 years) to the existing magnet and significantly expand the repertoire of the modern experiments that can be performed on it. The new Avance NEO console will enhance sensitivity and stability necessary for complex experiments. The new generation TCI probe will bring significant improvements to 1H/13C sensitivity for samples in high ionic strength physiological solutions and new 19F capabilities enabling state-of-the-art experiments for characterisation of interactions, conformational dynamics and structure of biomolecular systems. TXO cryoprobe will bring new capabilities for 13C and 15N detections enabling cutting edge experiments for characterisation of intrinsically disordered proteins, large biomolecular complexes and metalloproteins