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

生物分子系统在原子分辨率上的三维结构对于详细了解生物过程非常重要，目前主要通过两种实验技术来确定：x射线晶体学和核磁共振波谱学。但特别是后一种方法，由于在某些情况下甚至提出了完全错误的折叠，因此仍然存在对所得模型可靠性的争论。作为验证的新标准，我们建议使用量子化学计算的核磁共振化学位移。这些化学位移高度依赖于结构，实验值和理论值之间的偏差可能会识别出错误的褶皱，甚至是整体正确结构中的小问题。我们将利用我们在基于片段的量子化学方法方面的专业知识，使大型蛋白质和DNA/RNA结构及其复合物的计算成为可能，这些结构的大小使标准方法无法使用。通过结合适当水平的理论和基础集，同时考虑溶剂效应和构象平均，我们希望获得生物分子结构评估所需的精度，并结合大规模研究的计算效率。最后，所得到的集成软件将与核磁共振波谱学家和药物化学家合作应用于医学兴趣的特定目标。

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.