Mass spectrometry of proteins

这项建议是关于将质谱学应用于蛋白质研究的研究。质谱仪是用于检测和识别痕量物质的科学仪器。在质谱仪中，分子带电形成离子，然后根据它们的质量与电荷的比例在真空中分离这些离子。直到最近，才有可能将像血红蛋白这样的大蛋白质分子制成离子，并将它们注入真空中。这里提出的基础工作将检查真空中蛋白质离子的性质，并将它们与蛋白质在溶液中的性质进行比较，在溶液中它们执行其正常的生物功能。在某些情况下，真空中的蛋白质可以保持其溶液性质。如果这通常是正确的，那么质谱仪可以用来快速、灵敏、具体地研究蛋白质与其他物种的结合。具体地说，我们将检查血红蛋白离子的属性，以及导致疾病的Hb突变对这些属性的影响。我们将研究一类被称为“分子伴侣”的小分子药物在真空中与蛋白质结合的性质。质谱学可能为鉴定伴侣分子提供一种新的方法。我们将研究二氧化碳与血红蛋白等蛋白质的反应。长期以来，人们一直知道这是一种可能的二氧化碳在血液中的运输方法，但还没有详细的量化。最后，我们将研究在蛋白质离子中加入控制数量的水分子的影响，以确定对蛋白质离子折叠的影响。这项工作将为研究蛋白质在医学、制药和生物技术中的应用开辟新的途径。加拿大将至少在两个方面受益。拟议的工作将在对这种高素质人员有强烈需求的领域培训学生和博士后研究员。任何知识产权都将归不列颠哥伦比亚大学所有，因此将留在加拿大。

This proposal is for research in mass spectrometry applied to the study of proteins. Mass spectrometers are scientific instruments used to detect and identify trace substances. In mass spectrometers, molecules are electrically charged to form "ions" and the ions are then separated in vacuum according to their ratios of mass to charge. Only recently has it become possible to make ions of large protein molecules, like hemoglobin, and inject them into vacuum. The fundamental work proposed here will examine the properties of ions of proteins in vacuum and compare them to the properties of the proteins in solution, where they carry out their normal biological functions. In some cases, proteins in a vacuum can retain their solution properties. If this is generally true, then mass spectrometers can be uses to study binding of proteins to other species in a fast, sensitive specific way. Specifically we will examine the properties of hemoglobin ions, and the effects on these properties of mutations to Hb that cause disease. The properties of a class of small-molecule drugs called "molecular chaperones" binding to proteins in vacuum will be investigated. Mass spectrometry may provide a new method to identify chaperone molecules. The reaction of carbon dioxide with proteins like hemoglobin will be studied. This has long been known to be a possible method of transport of CO2 in blood, but has not been quantified in detail. Finally we will investigate the effects of adding controlled numbers of water molecules to protein ions, to determine the effects on folding of the protein ions. This work will lead to new approaches to study proteins for applications in medicine, pharmacy and biotechnology. Canada will benefit in at least two ways. The proposed work will train students and postdoctoral fellows in a field where there is a strong demand for such highly qualified personnel. Any intellectual property will be owned by the University of British Columbia, and thus will remain in Canada.