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The fingerprints of molecules

Prof. Heiko Möller is head of the NMR Core Facility, a centre at the University of Constance that focuses on magnetic resonance spectroscopy where fingerprints of molecules are taken. The highly sensitive analysis instruments are used by his group of researchers for research projects on subjects ranging from severed visual nerves, cancer protection and the rapid identification of anthrax bacteria.

Heiko Möller has been junior professor of “NMR spectroscopy of complex molecular systems” at the University of Constance since 2004. © University of Constance

"Basically it is a very complex thermos flask," said Prof. Heiko Möller describing the principle of "his" nuclear magnetic resonance imager (NMRI). Since 2004, when he became junior professor at the University of Constance, he has been in charge of a pool of highly sensitive NMRIs, which are a key technology for the analysis of molecule structures. "NMR imaging is paramount, nothing works without it," said the chemist who heads up the "NMR spectroscopy of complex molecular systems" research group. In autumn 2009, the NMR systems owned by individual laboratories located on different floors were pooled and set up in a specific work area on the M5 floor of the University of Constance. A special air-conditioned environment that is free of ground vibrations was put in place to house the systems, which can best be described as barrel-shaped machines with a sensitive inner life. The five spectrometers - along with two additional machines that are still waiting to be moved to the new area - are not exclusively used by Möller's group of researchers, but are at the disposal of all scientists at the University of Constance who investigate molecular structures and the interaction of molecules. The NMR Core Facility is a kind of service centre. Möller's research is not only restricted to the science related to NMR imaging and its further development.

The chemist pursues own projects, both with partners at the University of Constance and elsewhere. One of Möller's research projects focuses on neurolin, a protein that plays a key role in the regeneration of nerve cells. A few years ago, the Constance biologist Prof. Claudia Stürmer and her research group were trying to find out why a goldfish whose optic nerve had been severed was able to see again after six weeks. "The optic nerves "know" how they need to grow from the retina of the goldfish to the brain. A key partner in this process is the protein "neurolin"," said Möller summarising his research.

A close look at biomolecular interactions

At present, Möller’s doctoral student Zarko Kulic is working on the determination of the three-dimensional structure of neurolin, which is considered to be the key to its biological function. The analysis is carried out with NMR imagers. A protein solution is transferred into a vial and analysed in the imager, whose core part is a supraconductive magnet hanging in liquid helium with a temperature of minus 269°C. The helium is contained in a thermos flask-like container submersed in liquid nitrogen at minus 169°C. The nitrogen container is also surrounded by a “thermos flask”. The repeated vacuum isolation explains why the measurement devices are so huge. The device at the University of Constance, a Bruker AVANCE III 600 MHz spectrometer, has a diameter of around one metre, a height of around two metres and weighs 1.5 t. The supraconductive magnet generates extremely strong magnetic fields that cause the nuclei of molecules to orient themselves in a specific direction. The energy difference between the two potential orientations, with or against the magnetic field, is made visible by the NMR spectrometer.

Since all atoms of a molecule have a characteristic environment – a hydrogen atom can be bound to a carbon or nitrogen atom, for example and the carbon can bind to one or several oxygen atoms – NMR spectrometry reveals the “fingerprint of a molecule”, as Heiko Möller puts it. This helps the researchers to precisely differentiate the molecules from one another. In addition, the spectra provide a broad range of information about the chemical connection of the molecules under analysis as well as their interactions with their environment. Heiko Möller describes his research interest as the “investigation of biomolecular interactions”. These investigations explain how a pharmaceutical substance, a small molecule, interacts with a large protein such as a protein receptor. In a cooperative project with Altana (now Nycomed), Möller’s group of researchers was able to identify the area of a pharmaceutically active molecule that is essential for it to bind to an enzyme of the inflammation cascade.

The three-dimensional structure is a key feature in the biological function of a molecule: Producing a 3D picture of the molecule requires more than just the sequence of amino acids in a protein molecule. The way the thread of amino acids tangles up is of equal importance. In order to find out more, the researchers need to carry out experiments involving proteins produced in bacteria. This is a very time-consuming process, which can take up to several weeks. In many cases, one experiment is not enough and the researchers have to carry out 20 or 30 experiments.

In contrast to the determination of the structure of molecules using X-ray diffraction, NMR spectrometry has the advantage that the expressed protein does not need to crystallise. However, although it is not yet clear whether it actually does crystallise, crystals are a prerequisite for X-raying. X-rays have not yet proved their efficacy with neurolin, whereas NMR has. “The two methods complement each other in some areas, but there are also areas that can only be investigated using either one or the other method,” said Möller. The fact that he prefers to work on biological research projects is down to his personal preferences. Asked why he has chosen neurolin as a major research focus, he explained: “I find the fact that goldfish are able to see again extraordinary.” He also finds it exciting to see the protein, which is a surface receptor, extending its protrusions into the extracellular space to interact with partners that provide the nerve cell with information on the direction towards which it needs to grow. An analysis as to how this works now needs to be carried out.

Diagnostics system for anthrax bacteria

The researchers also focus on other equally exciting projects: one of Möller’s PhD students is working on molecular design. He is assembling molecules that imitate a protein that may well be able to provide protection against cancer some time in the future. In a cooperative project with the Berlin-based Max Planck Institute of Colloids and Interfaces and the Basel-based Tropical Institute, Möller’s research group is working on a diagnostics system for the identification of anthrax bacteria. Heiko Möller has excellent communication skills, something that is vital for his job, because many chemists still lack detailed knowledge of the versatility and capacity of NMR spectroscopy. “The fact is that there are too many methods that are far too complicated, makes it difficult for scientists to chose the best method for their research topics.”

When he started his career as junior professor at the University of Constance, his communication skills helped him integrate quickly with his new colleagues at the faculties of chemistry and biology. However, the “fact that the Constance biologists and chemists work closely together has made this task far easier,” admitted Möller adding “from the word go, the working atmosphere was exactly as I would have wished and this is still the case today.”

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/the-fingerprints-of-molecules