Marius Clore, G: Adventures in Biomolecular NMR

My NMR career started in 1980 when I joined the Division of Molecular Pharmacology at the Medical Research Council’s National Institute of Medical Research (NIMR) located in Mill Hill, London. I had been recruited 18 months previously by the director of NIMR, Sir Arnold Burgen, while still a medical student at University College Hospital Medical School, on the basis of the work I had published on cytochrome oxidase and other metalloproteins, largely involving low temperature transient kinetics. At the time that I was interviewed at NIMR in January 1979 I had no intention of going into NMR but was principally interested in the application of a variety of spectroscopic and kinetic techniques to study the flow of electrons in the respiratory pathway. NIMR, however, did not have the necessary instrumentation, and Sir Arnold Burgen suggested that I take up NMR. Since I had a strong mathematical bent, this was not too difficult, particularly as at the time, the number of NMR experiments that could be carried out on proteins was rather limited. All of this was very fortunate since it enabled me to fully participate in the development of NMR as a significant tool in structural biology and one that could be used to determine the three-dimensional structures of biological macromolecules in solution at atomic resolution. When I joined NIMR in August 1980, it was quite difficult, with the 270-MHz spectrometer then available to us, to even assign a simple dinucleotide such as NAD. And while it was clear that, in principle NMR could be used to determine three-dimensional structures of proteins, the path to accomplishing that was far from clear or evident. Indeed, I remember a heated discussion with Arnold Burgen when he told me in no uncertain terms that solving structures of proteins by NMR would never be feasible and that I was wasting my time. The progress that NMR has made in the last 30 years is simply astounding and never ceases to amaze, and I suspect that the end is nowhere near in sight. Indeed, just recently we succeeded in determining the three-dimensional structure of a protein known as enzyme I, a 128-kDa dimer, and its 146-kDa complex with its partner protein HPr,1 which only a few years ago would have been unimaginable. Further, using paramagnetic NMR, an old idea with a new twist, we have shown that it is possible to detect, characterize, and even directly visualize sparsely populated states of macromolecules that are invisible to conventional structural biology methods including conventional NMR spectroscopy and X-ray crystallography.2,3 In this brief overview, I summarize the developments along the way that I have participated in and that have led to these current advances.