Ultrahigh resolution NMR: citius, altius, fortius

Understanding the structures and behaviour of molecules is of critical importance in understanding the world around us, and in using chemistry to help us survive and prosper in that world. The single most useful method for determining molecular structure is NMR spectroscopy. Every hydrogen atom in a molecule - and most molecules contain many - produces a family of signals known as a multiplet. The position of the multiplet within the spectrum (the chemical shift) depends on the local chemical environment of the atom; the multiplet structure depends on its magnetic interactions (scalar couplings) with nearby atoms. As our understanding of chemistry and biochemistry advances, the species we need to study increase in size and complexity. The number of NMR signals grows accordingly, leading to very crowded NMR spectra that can be difficult or even impossible to interpret. Chemists and life scientists fight a continual battle to extract structural information from the complex sets of overlapping multiplets that are found in most NMR spectra.

This proposal describes a family of new experimental methods that enhance the speed, efficiency, and scope of NMR, by building on recent developments in "pure shift" NMR, which suppresses the effects of magnetic interactions and hence greatly simplifies spectra. For the most part the new methods trade sensitivity, which with recent advances in instrumentation is no longer a limiting factor for most samples, for speed, improving the efficiency with which spectrometer time is used, and enabling detailed structural information to be obtained on chemical systems that currently are too complex to be studied by solution state NMR. The common thread is that all these developments are focused on increasing the information bandwidth of NMR experiments - increasing the amount of structural information obtainable per unit time. The net result will be both to enable more chemical information to be delivered within existing spectrometer resources, and to make it possible to attack the most challenging structural problems within practical timeframes. The key tools that will be used are control of coupling interactions and tailored data sampling. Both technologies are beginning to find application in chemical NMR spectroscopy, but neither has come close to realising its full potential, and synergies between them are almost entirely unexploited. In combination they should enhance both the throughput and the power of chemical NMR in laboratories world-wide, in both industry and academia.

These new methods will find use across a wide range of academic research areas and industrial sectors including chemistry, biochemistry, biology, pharmaceuticals, healthcare, agrochemistry, and flavours and fragrances.

Who will benefit from this research?

NMR is a key underpinning technology for many of the UK's major wealth-generating industries, including pharmaceuticals, petrochemicals, fine chemicals and biotechnology, and an essential component of almost all research in synthetic chemistry. It is vital in the development of healthcare technologies, in particular for drug development and pharmaceutical process development, and throughout the chemical industry. NMR is used in chemical, biological and medical research, in academic, industrial and government laboratories, as the primary method for the determination of molecular structure and dynamics. For the great majority of these users, proton NMR is their primary tool, and almost all applications of proton NMR stand to benefit from the improvements in spectral resolution and information bandwidth that are planned here.

How will they benefit from this research?

We propose to design more powerful tools for NMR spectroscopy, pushing back the limits of the method substantially and equipping both academic researchers and core UK industries with enhanced spectral resolution and faster sample throughput. The new methods will produce simpler spectra that make structural information both more readily accessible, and more amenable to automated analysis, than is currently the case. The new family of methods can be implemented on standard commercial spectrometers, with no need for hardware modification. Equipping researchers with higher resolution and more time-efficient NMR tools will enhance wealth generation in all of the sectors noted above, and impact on health through improved methods for the characterisation of potential drugs and APIs, for the development and regulatory approval of new processes for the production of APIs, and for the analysis of biofluids in toxicology and metabolomics. Our results will be made freely available on the web, enabling early adoption by industrial and academic users alike, and we will collaborate with instrument manufacturers to minimise barriers to the implementation of the new experiments. There will be a number of secondary impacts. The researcher co-investigator, Dr Kiraly, will add a thorough grounding in the practicalities of new technique development in NMR to his very broad experience of the chemical application of established methods. This is in addition to building transferable skills in organisation, communication, critical and creative thinking, and exploitation of information technologies that are fundamental to research in the physical sciences. We will train researchers in collaborators' laboratories in pure shift NMR methods, and will run an open workshop on such techniques in the second year of the work programme. On the evidence of past methodological research of this sort we expect a long useful life for the techniques developed: many of the previous experiments developed with EPSRC support are now in established use world-wide; INEPT, for example, was developed almost 40 years ago but is an essential building block in modern methods for solution phase structural biology.