SHARPER NMR: fast and accurate analysis of molecules, reactions and processes

核磁共振（NMR）光谱是一种非常有用的分析技术，其应用范围涵盖医学、生物学、地球科学、物理学和化学等科学领域。它可以在活生物体、固态材料或溶解在液体中的分子上进行。溶液态核磁共振是化学家的基本技术。它已经存在了70年，但在发展、改进和提高效率方面没有任何放缓的迹象。核磁共振与其他光谱学的区别在于，作为核磁共振实验对象的原子核（或我们通常称之为自旋）的激发态的寿命。它们的寿命在毫秒到秒的量级上，这使得科学家们能够在信号采集之前，或者现在在信号采集过程中，设计出精心设计的自旋操纵方法。这些操作的目的是获得有关分子的结构或化学状态的特定信息，包括与其他分子的相互作用。这些操作很重要，原因有几个：（i）有时有太多的东西要看，我们需要简化NMR光谱，以便获得我们需要的信息。(ii)NMR是相对不敏感的技术，并且与其他分析技术（例如质谱法（MS））相比，需要大量的材料（通常为毫克量，与足以用于MS的微克、纳克或甚至皮科相比）。(iii)在其标准实现中，NMR可能太慢，无法监控毫秒到秒级的快速过程。(iv)理想情况下，溶液状态NMR是在均质样品上进行的，标准技术难以提供关于非均质系统的高质量信息，例如表征在两种不混溶液体的界面处发生的过程，该提议解决了上述困难，并旨在设计新颖的NMR技术，该技术允许在这种情况下获得信息。目前尚不可能（例如异构系统），或在效率（节省时间）和所获信息质量方面对现有技术带来明显改进。NMR参数的准确性将得到提高，这些参数最终被解释为提供化学结构、非线性化学反应或确定分子大小。重点是（i）监测快速化学反应和（ii）表征分子大小和（iii）超越分子的一级结构（单个原子相互连接的顺序），以了解原子如何在三维空间中排列（构象，三级结构）。这些信息对于我们合理化分子间相互作用（例如药物与生物大分子的相互作用）的能力至关重要。所提出的技术的另一个重要方面是，它们可以应用于复杂的系统。传统上，NMR在研究纯化合物方面非常出色，但直到今天，仍难以将它们作为混合物的一部分进行研究。在真实的生活中，从混合物中分离出单个分子并不总是可能的，许多行业必须学习如何有效地处理混合物。我们将与一家台式NMR光谱仪制造商合作，将开发的技术直接应用于专业NMR实验室的通风柜和生产线。我们预计，我们将开发的新方法将应用于广泛的学术和工业研究。

Nuclear Magnetic Resonance (NMR) spectroscopy is a very useful analytical technique, which has applications across the range of sciences, including medicine, biology, geosciences, physics and chemistry. It can be performed on living organisms, solid state materials, or molecules dissolved in liquids. This proposal focusses on the solution state NMR spectroscopy.Solution state NMR is a bread and butter technique for chemists. It has been around for 70 years, but does not show any sign of slowing down in its development, improvement, and increased efficiency. What distinguishes NMR from other spectroscopies is the longevity of the excited states of nuclei (or spins, as we often called them) that are subjects of NMR experiments. Their lifetime on the order of milliseconds to seconds allows scientists to design elaborate ways of spin manipulation before, or these days also during, signal acquisition. The purpose of these manipulations is to obtain specific information about the structure or the chemical state of the molecule, including interactions with other molecules.Such manipulations are important for several reasons: (i) sometimes there is too much to see and we need to simplify NMR spectra in order to access the information we require. (ii) NMR is a relatively insensitive technique and compared to other analytical techniques, such as for example mass spectrometry (MS), requires large amounts of material (typically milligram quantities, compared to micro, nano grams or even pico grams that are sufficient for MS). (iii) In its standard implementation, NMR can be too slow to monitor fast processes that are occurring on millisecond to second times scales. (iv) Ideally, solution state NMR is performed on homogeneous samples and standard techniques struggle to provide high quality information about heterogeneous system, e.g. characterisation of processes taking place at the interface of two immiscible liquids, or when a gas is bubbled through a solution.This proposal addresses the difficulties outlined above and aims to design novel NMR techniques that allow information to be obtained under circumstances where this is not as yet possible (e.g. heterogeneous systems), or bring evident improvements to existing techniques in terms of efficiencies (time saving) and quality of information obtained. Accuracy of NMR parameters, that are ultimately interpreted to provide chemical structures, characterise chemical reactions, or determine molecular sizes, will be improved. The focus is on (i) monitoring of fast chemical reactions and (ii) characterising molecular sizes and (iii) going beyond the primary structure of molecules (the order in which the individual atoms are connected to each other) to how the atoms are arranged in the three-dimensional space (conformation, tertiary structure). Such information is crucial to our ability to rationalise intermolecular interactions (e.g. interactions of drugs with biomacromolecules). Another important aspect of the proposed techniques is that they can be applied to complex systems. NMR has traditionally been very good in studying pure compounds, but to this day struggles to study them as part of mixtures. In real life situations it is not always possible to separate out individual molecules from mixtures, and many industries must learn how to deal with mixtures efficiently. We will work with a manufacture of benchtop NMR spectrometers to bring the developed techniques directly into fume hoods and production lines, out of the specialised NMR laboratories. We anticipate that the new methods we will develop will be applied across a wide spectrum of academic and industrial research.