ULTRAFAST MULTIDIMENSIONAL NMR: A NEW BIOMEDICAL TOOL

描述(由申请人提供)：就揭示分子系统本质的适用性而言，很少有分析技术能与多维核磁共振(核磁共振)的范围和能力相媲美。无论是新药的发现，蛋白质或核酸结构和动力学的研究，大脑新陈代谢的非侵入性监测，还是疾病的表征，当今科学领域的任何学科都离不开某种形式的多维核磁共振或核磁共振分析。然而，影响多维核磁共振技术的一个重要缺陷是，与其他光谱方法相比，它们需要相对较长的测量时间，与收集数百或数千次扫描有关。这将某些快速变化的系统，如蛋白质构象变化，流经色谱柱的分析物，或在生理条件下不稳定的生物大分子，置于其研究范围之外。同样不适合这种相对较慢的分析形式的还有目前可以通过单一组合化学分析以及混合成像/光谱学技术获得的数千种药理化合物，其中多维光谱相关性与体内空间定位方法相结合。作为本项目的一部分，我们计划开发一系列新的方案，这些方案应该能够在一次连续扫描中获得多维核磁共振谱。我们寻求在现代高场核磁共振和核磁共振仪器上进行这样的实验，从而为在相对较低浓度下表征分析物提供一个开放的资源。因此，这类研究的一个重要目标将集中在消除磁场涡流对光谱的影响，我们已经确认，磁场涡流在两个宽边成像系统以及低温冷却探头上进行超快多维核磁共振实验时，对观察到的伪影起着重要作用。该项目的另一个目标是将超快、多维和核超极化核磁共振方法结合起来。最后，还将利用超快核磁共振的基本原理，在高度不均匀或不稳定的磁场上记录单次扫描的一维和二维核磁共振谱。这反过来可能打开前所未有的高场混合磁铁在生物分子研究中的使用，使经济的台式核磁共振系统的开发成为可能，以及使相对不同的器官的体内磁共振波谱研究成为可能。总体而言，我们预计，通过帮助将任何多维光谱学或成像实验的获取时间缩短几个数量级，并通过在低分辨率磁体中获取高分辨率核磁共振谱，该项目将有助于在以某种方式受益于核磁共振和核磁共振光谱学成果的所有研究领域取得重要进展。

DESCRIPTION (provided by applicant): In terms of applicability to unravel the nature of molecular systems, few analytical techniques can rival the range and capabilities of multidimensional nuclear magnetic resonance (NMR). Whether dealing with the discovery of new pharmaceutical drugs, the investigation of protein or nucleic acid structure and dynamics, the non-invasive monitoring of brain metabolism or the characterization of disease, hardly any discipline in the realm of science proceeds nowadays without the aid of some form of multidimensional NMR or MRI analysis. Yet one important drawback affects multidimensional NMR techniques; namely, that by contrast to other spectroscopic methods, they require relatively long measurement times, associated with the collection of hundreds or thousands of scans. This places certain kinds of rapidly changing systems, like proteins changing conformation, analytes flowing through a chromatography column, or biological macromolecules that are unstable under physiological conditions, outside its realm of study. Also unsuitable to this relatively slow form of analysis are the thousands of pharmacological compounds that can currently be made available by a single combinatorial-chemistry assay, as well as hybrid imaging/spectroscopy techniques, where multidimensional spectral correlations are combined with in vivo methods of spatial localization. As part of the present project, we plan to develop a series of new schemes that should enable the acquisition of multidimensional NMR spectra within a single continuous scan. We seek to implement such experiments on modern high-field NMR and MRI instrumentation, thus providing an open resource for characterizing analytes at relatively low concentrations. An important goal of such research will thus concentrate on relieving the effects induced on the spectra by magnetic field eddy currents, which we have identified as playing an important role in the artifacts observed when ultrafast multidimensional NMR experiments are carried out on both widebore imaging systems, as well as on cryogenically cooled probeheads. Another goal of this project will be the combination of ultrafast multidimensional and nuclear hyperpolarization NMR methods. Finally, the principles underlying ultrafast NMR will also be exploited to record single-scan 1D and 2D NMR spectra on highly inhomogeneous or unstable magnetic fields. This could, in turn, open up the use of unprecedently high-field hybrid magnets to biomolecular investigations, enable the development of economic bench-top like NMR systems, as well as enable in vivo magnetic resonance spectroscopy investigations on relatively heterogeneous organs. Overall, we expect that, by helping to shorten the acquisition time of any multidimensional spectroscopy or imaging experiment by several orders of magnitude, and by enabling the acquisition of high-resolution NMR spectra in low resolution magnets, this project will help usher in important advances into all research areas that, in one way or another, have hitherto been benefiting from the fruits of NMR and MRI spectroscopies.