A Coordinated Infrastructure for NMR for the Physical and Life Sciences: Upgrade to the Ultra-high Field 950 MHz Spectrometer at Oxford

揭示细胞中数百万生物大分子的动力学和三维排列仍然是一项艰巨的任务。然而，如果我们要理解生命这种自然属性，我们就需要知道这些分子是如何组合和相互作用的。虽然大规模的努力，如人类基因组计划，已经为我们提供了组成生物体的一系列组件，但我们仍然离理解这些组件如何聚集在一起形成执行所有基本生物功能的分子机器还有一段距离。与工程师类似，我们需要“看到”组件的形状，以了解它们在功能组件中的作用和位置。核磁共振（NMR）光谱是目前唯一的方法，可以为我们提供生物成分的详细视图，其条件类似于生物体中发生的条件，甚至是活细胞本身。因此，NMR研究补充了其他依赖于创建固定组件的结构方法，如晶体学和电子显微镜。除了结构信息外，NMR还提供了关于这些成分随时间变化的动态行为的独特信息，这些信息可能与化学催化等事件有关，并对成分之间发生的关联进行了深入了解，这些信息补充了其他生物物理方法的信息。NMR仪器包括大型，强大且非常昂贵的磁铁和传输和记录实验信号的电子设备。在这项提案中，牛津大学请求英国研究委员会的支持，以升级我们现有的超高场950 MHz NMR系统，该系统具有英国最强大的磁体，并配备最新一代的高灵敏度电子信号检测。这种所谓的“冷冻探针”升级将使测量信号提高约2-4倍，提高收集的实验数据的质量，并使更具挑战性的分子系统能够进行研究。再加上一个自动化配件，将允许全天候使用升级后的NMR系统，我们的建议代表了最具成本效益和效率的手段，提高尖端的NMR能力和能力在英国（拟议的升级约为53.5万英镑，而类似的新系统约为500万英镑）。一旦升级，950 MHz NMR系统的50%时间将提供给来自英国其他学术机构和行业的外部用户。特别是，我们的目标是帮助来自英格兰南部和威尔士的用户，牛津大学非常适合作为一个容易访问的区域NMR中心。

Uncovering the dynamics and three-dimensional arrangements of the millions of biological macromolecules in a cell remains a formidable task. Yet we need to know how these molecules assemble and interact if we are to understand the emergent property called life. Although large-scale efforts, such as the human genome project, have provided us with the sets of components that make up living organisms, we are still some way from comprehending how these components come together to form the molecular machines that carry out all the basic biological functions. Similar to engineers, we need to "see" the shape of components to understand their role and place in functional assemblies. Nuclear Magnetic Resonance (NMR) spectroscopy is currently the only method that can provide us with detailed views of biological components under conditions similar to those that occur in living organisms, or even in the living cell itself. As such, NMR studies complement other structural methods which rely on creating immobilised assemblies, such as crystallography and electron microscopy. As well as structural information NMR gives unique information about the dynamic behavior of these components over time, which can be related to events such as chemical catalysis, and insight about associations occurring between components that complements information from other biophysical methods.NMR instrumentation consists of large, powerful, and very expensive magnets, and electronics that transmit and record experimental signals. In this proposal, the University of Oxford requests support from the UK Research Councils to upgrade our existing ultra-high field 950 MHz NMR system, which features the most powerful magnet in the UK, with the latest generation of high-sensitivity electronics for signal detection. This so-called "cryoprobe" upgrade will boost the measured signal by a factor of ~2-4 enhancing the quality of experimental data collected and enabling more challenging molecular systems to be studied. Coupled to an automation accessory that will allow round-the-clock use of the upgraded NMR system, our proposal represents the most cost-effective and efficient means of increasing cutting-edge NMR capacity and capability in the UK (~£535K for the proposed upgrade versus ~£5M for a similar new system).Once upgraded, 50% of the time on the 950 MHz NMR system will be made available to external users from other UK academic institutions and from industry. In particular, we aim to assist users from the south of England and Wales, for which Oxford is well placed to serve as an easily accessible regional NMR hub.