The scope of this study is to open up new avenues of high-resolution NMR within the fields of functional genomics and structural biology by dynamic nuclear polarization (DNP). This technique should improve the sensitivity of liquid state NMR by orders of magnitude and could extend the application field of NMR structure determination to megadalton complexes by selective enhancement of specific regions of large proteins. This method has the potential to advance the frontiers of NMR in proteomics and drug discovery. The proposal aims at the development of a cutting-edge experimental test-setup to demonstrate the use of DNP for applications in structural biology. To this end, two DNP spectrometers (HF-DNP and shuttle DNP spectrometers) will be developed. I n parallel, the DNP mechanism at high magnetic fields for biological applications will be investigated and optimized methods will be developed by theoretical and numerical tools. The developed spectrometers and methods will then be used to investigate th e application of the DNP technique on a broad range of biological systems. The new method will be an indispensable enhancement of NMR for the study of folding dynamics, structures of soluble and membrane proteins, metalloproteins and ribozymes as well as RNA and DNA. Additionally the exploration of the feasibility of this method for high-field NMR spectroscopy will advance further method developments in magnetic resonance as well as their application in other fields, like medical and neuronal imaging, nanostructure and semiconductor research in material sciences, analytical chemistry and pharmaceutical drug screening. The outcome of this Design Study will lead to a recommendation for the construction of a prototype DNP spectrometer and an infrastruc ture based on this technology, accessible for European researchers. This will give Europe a leading role in DNP research and its applications to biological structure determination.
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