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My research is concerned with understanding the molecular foundations of medical conditions and the underlying biological processes. The goal is to understand the interactions of the biological macromolecules (proteins and nucleic acids) and their complexes participating in disease-related processes at atomic detail in order to identify and develop means for therapeutic intervention. For example, we are investigating the interactions of the prion protein, which can undergo a pathogenic conformational change leading to transmissible spongiforme encephalopathies including Creutzfeldt-Jacobs Disease (CJD) and BSE. We investigate the mechanism behind the pathogenic conformational change, which is not understood yet and knowledge of which would allow targeted development of novel therapeutic strategies. Further, we investigate the binding of the prion protein to other proteins in the organism on a structural basis to identify putative sites for drug interaction. In this context we are characterizing the structure of a highly potent, therapeutically anti-prion active antibody fragment in its complex with the prion protein. Knowledge of the detailes 3-dimensional structure is a mandatory prrequisite for optimizing highly promising drug candidates, such as therapeutic proteins. Prion diseases belong the group of protein misfolding diseases and thus fall into one group with Alzheimer´s disease and Parkinson´s disease, which are neurodegenerative diseases, too. The results obtained from our studies and the methods developed in this context will provide important novel insights into the general mechanism of neurodegnerative diseases and how to interfere with them. In particular studies involving therapeutically active proteins are expected to play an important role in clearing pathogenic protein conformations and regeneration of the organism.
Other fields of interest include flexible, disordered proteins (also called intrinsically disordered proteins), which from up to 30 % of the whole proteom and which participate in many biologically and medically relevant interactions, e.g. with other proteins or with nucleic acids. These proteins do not adopt a stably folded structure per se, but are highly dynamic in their nature. It has to be asked, however, whether these proteins represent entirely random conformational ensembles. Stuctural pre-organisation, which still leaves significant room for flexibility and global disorder, would on the other hand severely limit the space for conformational search. Such a scenario might account for recognition of other proteins and nucleic acids in complex molecular machineries, such as the transcription machinery. I am interested in understanding the physical and chemical foundations of binding events of such molecules and invesitagte to which extent this information can be used for therapeutic applications. A system of the described kind is the tat-protein of AIDS-causing HI-virus and its interaction with the viral RNA element TAR, which both represent interesting targets for drug develpment.
The research descibed above aims at the understanding of structural foundations of biomolecular interactions in health and disease. Stuctural information providing insights with atomic detail is today only available by crystallography and nuclear magnetic resonance spectrosopcy. In my research I apply mainly NMR spectroscopy to gain high resolution information about structure and interaction surfaces. However, the more complicated the system under investigation is, the more sides it has to be viewed at in order not to miss any details and to avoid overinterpretation of exeperimental data from one particular method. Therefore, I apply combinations of biophyiscal, but also biochemical and computational methods in my research. A main tool in our reseach is optical spectrocopy (CD, fluorescence methods including life time). My group has further gained expertiese in methods including dynamic light scattering of small proteins and protein folding states and micro-viscosimetry, which both provide information about hydrodynamic state of a protein / its complexes. Experimental information is often put together in the computer. Among other things, we are interested in developing algorithms which may be applied to protein design. We also use molecular dynamic simulations and biomolecular docking to address scientific problems. It shall further be mentioned that I also apply crystallography in collaboration with Dr. Martins and Prof. Dobbek and electron microscopy in collaboration with Dr Geimer at UBT. Finally, we have a number of collaboration who can perform biological essays.
If you are interested in my research, please do not hesitate to contact me.
