Diffusion-Ordered NMR Spectroscopy: Solving the Overlap Problem

核磁共振波谱是化学家用来确定未知化合物分子结构的最广泛的工具。它是一个非常通用和灵敏的工具，但它有一个主要缺点：它分析混合物的能力很差，所以它主要用于仔细提纯的单一化合物。由于自然界中许多最具挑战性的问题--以及合成化学家提出的许多问题--都是以混合物的形式呈现给我们的，因此人们花了大量的努力将混合物分离成它们各自的成分，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核磁共振信号来绕过这一限制，以便区分来自不同物种的信号。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，并将其应用于非常成功--但几乎总是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利用现有的DOSY高分辨率结构分析技术解决基本问题，即信号重叠问题。在DOSY中，进行了一系列实验，其中使用脉冲场梯度来使光谱中的信号以依赖于扩散速率的速率衰减，然后使用这组光谱来合成二维光谱，其中Larmor频率与扩散系数成图。在不同物种具有相同频率的核磁共振信号的情况下，很难区分单个信号作为场梯度的函数对信号强度的整体衰减的不同贡献。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(例如，血浆、脑脊液或尿液)相对较差。这一建议列出了两条互补的途径来解决重叠问题：第一，通过改变光谱测量的方式，使得核自旋之间的相互作用被抑制(去耦合)；第二，通过从关注单个信号的衰减(单变量分析)转向整个光谱的衰减(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).