Demystifying diseases: Using NMR to understand Covid-19 at the molecular level

“I just thought it seemed cool!” – the reason that Prof. Carlomagno chose to study NMR for her master’s research, back in 1992, is refreshingly light-hearted. But her fascination with the way the technology works is typical of many people who have made it their life’s work: “I started off really interested in the physics of NMR, and indeed I spent the early years of my career simply developing new experimental methods,” she says.

Nearly 30 years later, and her enthusiasm for NMR hasn’t dwindled. In fact, it’s stronger than ever: “In my career I’ve used many methods to probe molecular structures and interactions, such as electron paramagnetic resonance, X-ray crystallography, biochemical assays, mass spectrometry, and small-angle neutron scattering”, she says. “But time and again, I come back to NMR for its versatility and insight into interactions at the molecular level – I suppose it’s really my first love!”

Applying NMR to biomolecules

Prof. Carlomagno works at Leibniz University, Hannover, where she and her team of about 15 Ph.D. students, postdocs and technical staff focus on identifying new targets and ligands, to address diseases ranging from cancer to viral infections.

The Centre of Biomolecular Drug Research, also known as BMWZ, where she’s based, is relatively new, she explains: “BMWZ began life in 2011, when a group of chemists wanted to investigate the potential of natural products as drugs. Then in 2015 it was enriched with the program on NMR-based structural biology, and that was how I got involved.” By that time, Prof. Carlomagno’s focus had already expanded beyond ‘pure’ NMR methodology: “Over time I had become more interested in biology, and when I joined BMWZ my research program had already changed to using NMR to shed light on the interactions between biomolecules,” she says.

That interest in the biomolecular applications of NMR has proved valuable in her role at BMWZ, she says: “We’re applying NMR to very large assemblies of molecules in solution – primarily proteins, RNA, and the complexes between them. The beauty of NMR is manifold: you can adapt the experiment to ask a specific question; you can ‘zoom in’ to a particular part of a molecule; and you can study dynamics as well as structure. All this is unique to NMR.”

Elucidating how SARS-CoV-2 works

Prof. Carlomagno’s experience has proved particularly useful during the pandemic, as part of the Covid-19 NMR Consortium: “I’ve known the consortium head, Professor Dr Harald Schwalbe, for a long time – in fact, we both worked in the group of Professor Dr Christian Griesinger at the same time in the 1990s,” she says. “So, when I heard about the Consortium, I was only too happy to get involved.”

Within the Consortium, Prof. Carlomagno is focused on how SARS-CoV-2 (the causative agent of Covid-19) evades the host’s immune response, allowing it to hijack the host’s cellular machinery to make more copies of itself. “A theory is that one of the viral proteins interacts with its own messenger RNA, preventing it from degrading and giving it an advantage over the host’s mRNA. We’re trying to understand how this process works, and especially how the proteins and mRNA interact, both in solution and in the solid state.”

This point about solid-state NMR analysis of RNA-protein complexes is a pertinent one, because it is an area in which Prof. Carlomagno has particular expertise. “We’ve been using this method for quite some time in our studies of large biomolecules, because it allows us to obtain NMR spectra when the molecule is either difficult to get into solution or is embedded in a membrane. So, it’s a really useful addition to the toolbox for this sort of work.”

Extracting understanding from disorder

There is also another aspect of biomolecular science that Prof. Carlomagno addresses with NMR. She explains that in recent decades, biomolecules lacking a clear tertiary structure have become a topic of much interest: “These molecules look like spaghetti, they move around like spaghetti, but somehow they still manage to have important interactions.”

“These disordered structures are relevant to our work on SARS-CoV-2 because of a protein called Nsp1, which plays a key role in the infection ability of the virus,” she says. “The interesting thing about this protein is that part of it is well-folded, whereas another part is very disordered. In proteins with this topology, these two parts seem to have separate roles, with the molecule as a whole using a mix of enthalpic and entropic contributions to achieve binding. Part of our work has been to study how proteins can do this and yet remain so selective.”

And this is where NMR comes up trumps again. “Out of all the techniques used in structural biology, only NMR allows you to study disordered molecules such as this. It really is unmatched in its ability to examine molecules that adopt different shapes in solution, and I’m very keen to use it to find out more about the unusual properties of Nsp1.”

Collaboration versus competition

And what might ultimately come of this research? Prof. Carlomagno is cautiously optimistic: “Projects and plans always evolve as new results emerge – so it’s unwise to make long-term plans,” she says. “We definitely still have a lot of work to do in this project, but, once we’ve got a clear picture of the protein–mRNA interactions that are most important, the ultimate goal will be designing a drug to interfere with Covid-19. In the future, it’s going to be essential to have multiple strategies to deal with it, especially for those unable or unwilling to receive vaccination.”

And even though the Covid-19 NMR consortium has been running for less than two years, Prof. Carlomagno has seen first-hand the benefits of doing research this way: “For me, the great thing about the consortium has been that it overcomes the negative consequences of the competitiveness often present in science.”

“This has made a refreshing and very worthwhile change – we’re using the same techniques to study the same things, but as part of a team. So, with expert guidance from Prof. Schwalbe, we’ve been able to get through a vast amount of work more efficiently, leading to accelerated outcomes. For example, we’ve been able to publish results that simply wouldn’t have appeared if our groups had been working independently.”

Could this be a model for the rest of science? Prof. Carlomagno says it would need some careful thought. “Competition for funding and the rush to publication hinders easy collaboration among scientists within the same field more than ever these days; at the same time, a certain amount of friendly rivalry is good to keep you motivated,” she says. “But in certain circumstances, where the goal is well-defined and would benefit from a coordinated effort amongst a small group, then yes, I think that collaboration amongst scientists with the same expertise should be exploited more – provided the funding can be easily arranged, of course.”

The role of NMR instrumentation

And finally, Prof. Carlomagno is keen to stress the importance of the instrumentation in enabling new discoveries: “Although the focus of science is often on our research findings, I think we mustn’t forget the role of instrument manufacturers. It’s their continuous efforts to develop new tools with new capabilities that underpins our ability to address ever more complex and challenging questions”.

“So, I believe that access to the latest equipment is not only essential for generating new results, but also vital for pushing boundaries and making major progress in science.”

At the time of writing, Professor Dr Teresa Carlomagno was Professor of Structural Biology and Structural Chemistry at the Centre of Biomolecular Drug Research (Biomolekulares Wirkstoffzentrum, BMWZ) at Leibniz University, Hannover, Germany. Before this, she had appointments at the University of Frankfurt, the Scripps Research Institute in La Jolla, the Max Planck Institute for Biophysical Chemistry in Göttingen, and EMBL in Heidelberg, where she researched various aspects of NMR methodology and biomolecular sciences.

As of October 2021, Prof. Carlomagno was appointed to lead the Biomolecular Nuclear Magnetic Resonance (NMR) national facility at the University of Birmingham, UK.

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