950 MHz NMR spectrometer with cryo probe

结合X射线晶体学，冷冻电子显微镜和NMR光谱学的综合结构生物学如今为生理和疾病相关细胞途径的基本生物过程提供了分子细节。了解这些复杂的分子机制是不可能的静态结构，但关键需要了解功能重要的蛋白质，RNA及其复合物的构象动力学。核磁共振波谱是唯一能够以（近）原子分辨率描述生物大分子动态特性的方法，时间范围从皮秒到小时。为了研究蛋白质、RNA及其复合物在类似天然溶液环境中的分子机制，超高磁场下的NMR光谱对于提高信噪比和光谱分辨率至关重要。此外，约三分之一的人类蛋白质组包括固有无序区域和蛋白质（IDR/IDP），其通常在调节细胞过程中起重要作用，在通过液-液相分离形成无膜细胞器的调节中起重要作用，并且与人类疾病（从癌症到神经退行性疾病）相关。这些区域只能通过溶液NMR技术来解决，但由于其氨基酸组成的简并性，需要增加光谱分辨率。NMR硬件、NMR方法学、样品制备和同位素标记方法的不断发展为用溶液状态NMR研究生物医学相关的生物分子系统开辟了新的可能性。在本提案中，我们申请在Bayerische NMR-Zentrum永久安装950 MHz超高场NMR光谱仪。这是在与一个0.7毫米MAS固态核磁共振探针最近安装的1.2 GHz的光谱仪的附带建议。根据BNMRZ国际科学顾问委员会（SAB）的建议，我们计划在1.2 GHz仪器上保留50%的测量时间用于超快MAS固态NMR应用，以利用灵敏度和分辨率的显著改进。在1.2 GHz的溶液状态应用中测量时间的减少将由950 MHz仪器补偿，该仪器将专门用于溶液状态实验，支持越来越多的需要超高场溶液NMR测量的项目。

Integrative structural biology combining X-ray crystallography, cryo-electron microscopy and NMR spectroscopy nowadays provides molecular details for essential biological processes that underlie physiological and disease-linked cellular pathways. Understanding these complex molecular mechanisms is not possible with static structures but critically requires an understanding of functionally important conformational dynamics of proteins, RNAs and their complexes. NMR spectroscopy is the only method that can describe the dynamic properties of biological macromolecules at (near-) atomic resolution for timescales ranging from picoseconds to hours. To study molecular mechanisms of proteins, RNAs and their complexes in a native-like solution environment, NMR spectroscopy at ultra-high magnetic fields is essential to improve signal-to-noise and spectral resolution. Moreover, about a third of the human proteome comprises intrinsically disordered regions and proteins (IDRs/IDPs), which often play essential roles to regulate cellular processes, play important roles in the formation a regulation of membrane-less organelles by liquid-liquid phase separation and are linked to human disease, ranging from cancer to neurodegenerative disorders. These regions can only be addressed by solution NMR techniques, but require increased spectral resolution due to the degeneracy of their amino acid composition. Continuous developments in NMR hardware, NMR methodology and sample preparation and isotope labeling methods have opened up new possibilities to study biomedically relevant biomolecular systems with solution state NMR. In this proposal, we apply for the permanent installation of the 950 MHz ultra-high-field NMR spectrometer at the Bayerische NMR-Zentrum. This is in connection with an accompanying proposal for a 0.7 mm MAS solid-state NMR probe for the recently installed 1.2 GHz spectrometer. Following recommendations of the international Scientific Advisory Board (SAB) of the BNMRZ, we plan to reserve 50% of the measurement time at the 1.2 GHz instrument for ultrafast MAS solid-state NMR applications to take advantage of the outstanding improvements in sensitivity and resolution. The resulting reduction in measurement time available for solution- state applications at 1.2 GHz will be compensated by the 950 MHz instrument, which will be used exclusively for solution state experiments supporting the increasing number of projects that require ultra-high-field solution NMR measurements.