Oxygen-17 NMR spectroscopy of biological systems

核磁共振波谱是研究分子结构、动力学和化学键的一种强大的分析技术。在过去的几十年里，这项技术的发展已经彻底改变了化学和生物科学。然而，大多数成功的核磁共振应用于生物系统，如蛋白质和核酸，主要是基于核自旋量子数为1/2的原子核的检测，如H-1， C-13和N-15。另一方面，氧元素作为有机和生物分子中最丰富的元素之一，还没有很容易地通过核磁共振波谱法获得。这主要是因为唯一的核磁共振活性氧同位素O-17的核自旋量子数为5/2，被称为四极核。与常用的自旋为1/2的原子核不同，四极原子核是出了名的难以用核磁共振来研究的，因为它们通常会产生非常宽的核磁共振信号。因此，O-17通常被认为是“核磁共振不可见的”，特别是在生物大分子的背景下。我们最近的工作解决了这个具有挑战性的问题。我们已经开发了新的核磁共振方法，允许在固态和水溶液中检测生物大分子的高分辨率O-17核磁共振光谱。这种新的O-17核磁共振方法，作为现有的H-1、C-13和N-15核磁共振方法的补充，可以产生关于分子相互作用的独特信息。我们提出的研究计划的主要目标是将这些新的O-17核磁共振方法应用于几个重要的生物系统。特别是，我们将研究配体与血红素蛋白的结合，并检测与丝氨酸蛋白酶催化相关的酶促反应中间体。我们研究计划的最终目标是使所有主要元素（氢、碳、氮和氧）在生物分子中发现，通过核磁共振波谱可以平等地访问。我们希望通过展示O-17核磁共振在解决重要生物学问题方面的力量，更多的研究人员会考虑使用这种方法来解决自己的研究问题。预计未来5年将培养20名HQPs（4名博士、6名硕士、10名理学士）。

Nuclear magnetic resonance (NMR) spectroscopy is a powerful analytical technique for studying molecular structure, dynamics, and chemical bonding. The development of this technique over the past several decades has revolutionized chemical and biological sciences. However, most successful NMR applications to biological systems such as proteins and nucleic acids are primarily based on detection of atomic nuclei with a nuclear spin quantum number of 1/2 such as H-1, C-13, and N-15. On the other hand, the oxygen element, being one of the most abundant in organic and biological molecules, has not yet been readily accessible by NMR spectroscopy. This is mainly because the only NMR-active oxygen isotope, O-17, has a nuclear spin quantum number of 5/2, known as a quadrupolar nucleus. Unlike commonly used spin-1/2 nuclei, quadrupolar nuclei are notoriously difficult to study by NMR because they often give rise to very broad NMR signals. As a result, O-17 is very often considered to be "NMR invisible" especially in the context of biological macromolecules. Our recent work has solved this challenging problem. We have developed new NMR methods that allow detection of high resolution O-17 NMR spectra for biological macromolecules both in the solid state and in aqueous solution. This new O-17 NMR approach, being complementary to the existing H-1, C-13, and N-15 NMR methods, can yield unique information about molecular interactions. The primary objective of our proposed research program is to apply these new O-17 NMR methods to several important biological systems. In particular, we will study ligand binding to heme proteins and to detect enzymatic reaction intermediates related to serine protease catalysis. The ultimate goal of our research program is to make all major elements (H, C, N, and O) found in biological molecules equally accessible by NMR spectroscopy. We hope that by demonstrating the power of O-17 NMR in solving important biological problems, more researchers will consider to use this method for solving their own research problems. It is anticipated that, in the next 5 years, a total of 20 HQPs (4 PhD, 6 MSc, and 10 BSc students) will be trained in this research program.