Structure Evaluation of Biochemical Systems Based on NMR Chemical Shift Calculations with a Fragment-Based Quantum Chemical Approach

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The 3D structures of bio-molecular systems in atomic resolution, important for the in-detail under-standing of biological processes, are determined nowadays mainly with two experimental techniques: X-ray crystallography and NMR spectroscopy. But especially for the latter method there is still debate about the reliability of the obtained models since in some cases even totally wrong folds were pro-posed. As a new criterion for validation, we propose here to use quantum chemically calculated NMR chemical shifts. These chemical shifts are highly dependent on the structure and the deviation be-tween the experimental and theoretical values could identify wrong folds or even small problems in overall correct structures. We will use our expertise in fragment-based quantum chemical methods to make such calculations possible also for large protein and DNA/RNA structures and their complexes, whose sizes preclude the usage of standard methods. By combining appropriate levels of theory and basis sets but also taking solvent effects and conformational averaging into account, we hope to obtain the needed accuracy for bio-molecular structure evaluation combined with a computational efficiency for large-scale investigations. Finally, the resulting integrated software will be applied to specific targets of medicinal interest in cooperation with NMR spectroscopists and medicinal chemists.