Hyperfine Resolution and Advanced Structural Analysis to Enable Next-Generation Molecular Science

在石油等日常材料、木质素(某些生物燃料的前体)、合成聚合物和塑料等生物降解材料、合成聚合物和塑料中存在着极其广泛的分子种类，当然，活着的生物体有许多不同类型的小分子(激素、细胞壁脂、氨基酸、糖)以及许多大分子，如蛋白质和DNA。为了让科学家能够将这些分子用于新技术，所有这些分子都需要详细的分子结构确定，而质谱学是分析技术工具箱中的关键工具。傅里叶变换离子回旋共振(FTICR)质谱计是一种特别先进的质谱计，广泛用于超高分辨率、质量精度和需要对分子进行详细结构分析的实验。此外，FTICR质谱仪是用途最广的质谱计，具有许多不同的方法来观察和表征分子的结构细节。拟议的仪器还将包括以不同方式分割离子的能力，从而能够区分不同分子结构但不同质量的分子(即异构体--生物分子中非常常见的异构体，例如顺式和反式脂肪或不同类型的糖)。这台新仪器还将增加大幅改进的仪器控制和数据分析软件和电子设备，这也将使数据质量和采集速度提高约2-3倍。此外，我们将与这些仪器的唯一商业制造商Bruker合作，开发几项新技术，以提高我们分析复杂分子混合物的能力。与布鲁克的合作将通过为这些开发提供直接进入市场的途径(具有适当的知识产权保护和许可)来加强这项研究的影响，这将使这些开发能够通过布鲁克已建立的商业分销路线迅速推广到未来和现有的FTICR用户。如上所述，这一新仪器将极大地扩展我们研究化学和生物学的能力，但它也将极大地提高我们在天然、活跃的生物环境中研究药物小分子的能力，无论是天然的还是合成的。例如，蛋白质随着年龄的增长而变硬的部分原因是被称为糖基化的与糖相关的修饰，随着时间的推移，糖基化在关节中的胶原蛋白上积累，这在糖尿病患者中尤其常见，糖尿病患者每季度通过HbA1c临床测试进行测量。这一仪器将使我们能够更好地研究这种修饰的形成和位置依赖的生化机制，以便我们能够帮助医学界了解在老龄化人口中改善健康生活的替代方案。该仪器还将提高我们研究生物燃料生产和潜在下游环境影响的能力，从而提供设计生产以将负面影响降至最低的能力。该仪器将作为可持续资助的国家合作质谱学资源，由经验丰富的学者和工业家组成的战略咨询委员会监督，并将通过各种机制向科学界和工业界更广泛的科学界提供。项目的优先顺序将基于1)科学的卓越，2)EPSRC的职权范围，3)影响力，4)早期职业研究人员的准入，以及5)所有其他项目。新仪器将每年至少250天用于这些优先的协作或用户研究项目。

An extremely wide range of molecular species are present in everyday materials such as petroleum, biodegradation materials such as lignin (a precursor to some biofuels), synthetic polymers and plastics, and of course, living organisms have many different types of small molecules (hormones, cell-wall lipids, amino acids, sugars) as well as many large molecules like proteins and DNA. For scientists to be able to use these molecules for new technologies, all of these molecules require detailed molecular structure determination, and mass spectrometry is a key tool in the toolbox of analysis techniques. The Fourier transform ion cyclotron resonance (FTICR) mass spectrometer is a particularly advanced type of mass spectrometer widely used for ultra-high resolution, mass accuracy, and experiments requiring detailed structural analysis of molecules. Furthermore, the FTICR mass spectrometer is the most versatile type of mass spectrometer with many different ways to observe and characterise the structural detail of molecules. The proposed instrument will also include the ability to fragment ions in different ways thus providing the ability to distinguish molecules which differ in their molecular structure, but not their mass (i.e. isomers - which are extraordinarily common in biomolecules, for example cis- versus trans- fats or different types of sugars). This new instrument will also add substantially improved instrument control and data analysis software and electronics which will also improve data quality and acquisition speed by about a factor of 2-3.Additionally, in collaboration with the only commercial manufacturer of these instruments, Bruker, we will develop several new technologies that will improve our ability to analyse complex mixtures of molecules. This collaboration with Bruker will enhance the impact of this research by providing a direct route to market for these developments (with appropriate intellectual property protection and licensing), which will allow these developments to be rapidly rolled-out to future and existing FTICR users via Bruker's established commercial distribution routes. This new instrument will substantially expand our capability to study chemistry and biology, as above, but it will also greatly improve our ability to study small drug molecules, whether natural or synthetic, in their natural, active biological environment. For example, the 'stiffening' of proteins with age is partially due to sugar-related modifications called glycation, which accumulate over time on collagen in the joints, and is particularly common in diabetics which is measured quarterly with the HbA1c clinical assay. This instrument will allow improved study of the biochemical mechanism of formation and positional dependence of such modifications so that we can help inform the medical community on alternatives to enhance healthy living in an aging population. The instrument will also improve our ability to study biofuel production and potential downstream environmental impacts - thus providing the ability to design production to minimize the negative impacts. This instrument will be set up as a sustainably funded national collaborative mass spectrometry resource, overseen by a Strategic Advisory Board of experienced academics and industrialists and will be made available through various mechanisms to the wider scientific community in science and industry. Projects will be prioritized based on 1) scientific excellence, 2) EPSRC remit, 3) impact, 4) early career researcher access, and 5) all other projects. The new instrument will be made available for these prioritized collaborative or user research projects for at least 250 days per year.