Diffusion-Ordered NMR Spectroscopy: Solving the Overlap Problem

核磁共振（NMR）光谱是化学家最广泛使用的确定未知化合物分子结构的工具。它是一种非常通用和灵敏的工具，但它有一个主要缺点：它在分析混合物方面很差，所以它主要用于仔细纯化的单一化合物。由于自然界中许多最具挑战性的问题--以及许多由合成化学家提出的问题--都是以混合物的形式呈现给我们的，因此我们花费了大量的努力将混合物分离成它们各自的组分，以便能够识别它们。扩散有序光谱（DOSY）试图通过分离不同大小分子的NMR信号来克服这一限制，从而可以区分不同物种的信号。在过去的10年里，我们的研究小组和其他人开发了这项技术，并成功地将其应用于相对简单的混合物。在这个项目中，一名博士后研究员将解决DOSY高分辨率结构分析现有技术的基本问题，即信号重叠问题。在DOSY中，进行了一系列实验，其中脉冲场梯度用于使光谱中的信号以取决于扩散速率的速率衰减，然后使用光谱集来合成二维光谱，其中拉莫尔频率相对于扩散系数绘制。当不同的物质具有相同频率的NMR信号时，很难区分各个信号对作为场梯度的函数的信号强度的总体衰减的不同贡献。结果是DOSY对于信号很少重叠的简单混合物非常有效，但对于具有许多重叠信号的复杂混合物相对较差（例如，生物流体，如血浆、脑脊髓液或尿液）。首先，通过改变测量光谱的方式，从而抑制核自旋之间的相互作用（解耦），第二，通过从关注单个信号的衰减（单变量分析）改变到关注整个频谱的衰减（多变量分析）。

Nuclear magnetic resonance (NMR) spectroscopy is the tool most widely used by chemists for determining the molecular structures of unknown compounds. It is a wonderfully versatile and sensitive tool, but it has one major drawback: it is poor at analysing mixtures, so it is mostly used on carefully purified single compounds. Because many of Nature's most challenging problems - and many of those posed by synthetic chemists - are presented to us as mixtures, a great deal of effort goes into separating mixtures into their individual components so that they can be identified. Diffusion-ordered spectroscopy (DOSY) tries to get around this limitation by separating the NMR signals of molecules of different sizes, so that the signals from different species can be distinguished. Over the last 10 years our research group and others have developed the technique and applied it with great success - but almost always to comparatively simple mixtures. In this project, a postdoctoral research fellow will tackle the fundamental problem with existing techniques for high resolution structural analysis by DOSY, the problem of signal overlap. In DOSY, a series of experiments is performed in which pulsed field gradients are used to make the signals in a spectrum decay at a rate which depends on the rate of diffusion, and the set of spectra is then used to synthesise a two-dimensional spectrum in which Larmor frequency is plotted against diffusion coefficient. Where different species have NMR signals at the same frequency, it is extremely difficult to distinguish the different contributions the individual signals make to the overall decay of signal strength as a function of field gradient. The result is that DOSY works very well for simple mixtures, where signals rarely overlap, but comparatively poorly for complex mixtures with many overlapping signals (for example biofluids such as plasma, cerebrospinal fluid or urine).This proposal sets out two complementary routes to solving the overlap problem: first, by changing the way in which spectra are measured so that interactions between nuclear spins are suppressed ( decoupled ), and second by changing from focusing on the decays of individual signals (univariate analysis) to that of the entire spectrum (multivariate analysis).