Mark Rance - Scientific Career and Contributions

by John Cavanagh, Art Palmer, Walter Chazin and Andy Byrd

November 13th, 2020

Mark’s research career was as varied as it was pioneering. His first forays into the research world centered around wide-line deuterium NMR spectroscopy and the dynamics of lipid fatty acid chains in membranes. These studies, carried out in the Department of Physics at the University of Guelph during his PhD (1981) and subsequent appointment at the Division of Biological Sciences of the National Research Council of Canada (1981-1982), were the first to look at real biological systems rather than model bilayer systems. These efforts led to a deeper understanding of the physical state of biological membranes and helped address controversial questions concerning the mobility of fatty acid chains in the vicinity of membrane proteins.

A move to Europe was next on Mark’s agenda. Arriving at the ETH, Zürich in 1982 for post-doctoral work, he held a unique position split between the groups of Nobel Laureates Prof. Richard Ernst ((Laboratorium für Physikalische Chemie) and Prof. Kurt Wüthrich (Institut für Molekular Biologie und Biophysik) that was part of a unique arrangement sponsored by Bruker and the Swiss Government. At the time, this appointment was quite distinctive, bridging, as it did, the worlds of physical and biological sciences. Certainly, this period set the tone for the remainder of Mark’s career. The impact of his work in developing the double quantum filtered (DQF) COSY experiment cannot be overstated. In a landmark 1983 publication in BBRC, Mark introduced this powerful technique and its expanded potential, particularly in the study of proteins, to the burgeoning field of biomolecular NMR. The DQF-COSY paper has been cited well over 2500 times and was re-published in a special section of the journal, devoted to the top ten most cited papers in the history of the journal.

Returning to North America in 1984, Mark became part of the Protein NMR Laboratory headed by Peter Wright in the Department of Molecular Biology at The Scripps Research Institute in La Jolla, CA. There then followed a particularly prolific period in the 1990’s and early 2000’s, initially at Scripps and then after his move in 1996 to the University of Cincinnati Medical School. For the most part, Mark devoted his energies into developing new and/or improved NMR techniques for studying biological systems. At the same time, he more fully began to explore his interest in measuring solution-state dynamic parameters and in employing advanced computational methods. Much of his initial developmental work in the 1990’s focused on TOCSY experiments, working towards improved isotropic mixing schemes. He was particularly keen on enhancing general sensitivity by removing deleterious relaxation effects or by improving bandwidth. In the middle of this work he discovered a beautifully simple way of improving the sensitivity of TOCSY experiments. This ‘preservation of equivalent pathways’ approach was found to improve sensitivity such that data could be collected in approximately half the time compared to conventional experiments. It then became apparent that this methodology was not limited to TOCSY-type experiments but could provide similar sensitivity enhancement when incorporated into the most common heteronuclear, multi-dimensional NMR experiments employed for resonance assignment and many of the most popular spin relaxation experiments. It is now rare to see such experiments performed without this unassuming but powerful augmentation.

Dynamics began to play a bigger role in Mark’s endeavors, beginning with a 1987 paper on cancellation of exchange effects in multiple quantum NMR spectra. While evaluating the backbone and side-chain dynamics of various proteins with countless friends and collaborators, he was instrumental in developing improved methods for making such measurements. Two examples have become widely, if not universally, adopted. The relaxation-compensated CPMG pulse sequence and various adaptations thereof have made it possible to study motions on the microsecond-millisecond timescale in a wide variety of applications, including enzyme dynamics, studies of lowly-populated excited states, and intrinsically disordered proteins. Also, methodology for suppressing certain cross-correlation effects is used commonly in experiments for measuring spin-spin relaxation rates.

Of late Mark split his time between applications and methods development. He studied the dynamics of nuclear receptor proteins and homeodomain proteins bound to DNA. These were challenging systems to attack, because the entropic contributions, including the presence and influence of side-chain conformational dynamics, are especially difficult to estimate based on structural information. Mark concentrated on combining experimental and theoretical studies to this end and was trying to better understand the contribution of these allosteric effects. He also continued his work on better quantitating chemical exchange phenomena, assisting in developing expressions to improve accuracy and efficiency in the analyses of kinetic and exchange data.

Of course, Mark provided a much-needed helping hand in writing the 2nd Edition of the textbook “Protein NMR Spectroscopy: Principles and Practice”. His depth and breadth of the subject matter was only part of his contribution. Mark always provided a boost to his fellow co-authors with his scientific insights of course, but perhaps more importantly, his always calming demeanor made everyone better in their efforts. The 3rd Edition will be better for Mark’s presence.

Wide-line deuterium NMR and membranes. The DQF-COSY for small molecules and proteins. Sensitivity enhanced NMR. Relaxation-compensated CPMG. Suppression of cross-correlation effects. “Protein NMR Spectroscopy: Principles and Practice”.

Not bad, Mark.