Novel Implementations, Analytical Targets, and Mechanistic Studies of Negative Ion Electron Capture Dissociation

在化学系化学测量和成像项目的支持下，密歇根大学的Kristina Hakansson教授和她的团队正在努力提高我们表征分子化学结构的能力，特别是生物分子，如蛋白质。这种结构分析对于帮助我们理解复杂样品（如生物流体、细胞和组织）中分子的功能（和功能障碍）至关重要。Hakansson方法将电子附着到气态阴离子（带负电荷的分子）上，在称为负离子电子捕获解离（niECD）的过程中诱导目标分子的诊断分裂。由于电荷排斥，将电子（带负电荷）添加到阴离子（也带负电荷）是具有挑战性的。开发了这种方法后，Hakansson博士现在正在努力提高我们对niECD的理解，并扩大其适用性和可用性。该研究为生物分子结构表征提供了新的方法，对药物发现和增强对生物体分子基础的理解具有重要意义。参与的学生可以接触到高度跨学科的研究。Hakansson博士还致力于为中学生带来对这些概念的欣赏和更广泛的STEM机会，以提高他们在年轻时对科学方法的兴趣。Hakansson小组正在探索新的niECD仪器配置，包括扩展到基质辅助激光解吸/电离和纳米电喷雾电离。他们正在努力在高压电池中实现niECD，使其能够与傅立叶变换离子回旋共振（FT-ICR）以外的质量分析仪一起使用。为了更好地了解niECD的基本化学基础，他们正在采用两种方法(漂移管离子迁移率和FT-ICR的横截面积，或CRAFTI （FT-ICR的横截面积）来测试Hakansson博士最近的发现，紧凑的，可能是盐桥结构是有效的肽niECD所必需的。这些努力得到了分子模型和密度泛函理论计算的支持，特别关注新的分析物类别，如碳水化合物和脂类，最近由Hakansson小组发现，尽管不符合先前提出的两性离子机制，但它们会经历niECD。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Kristina Hakansson and her group at the University of Michigan are working to improve our ability to characterize the chemical structure of molecules, including especially biomolecules such as proteins. Such structural analysis is essential to help us understand the function (and dysfunction) of molecules in complex samples, e.g., biofluids, cells, and tissues. The Hakansson approach employs the attachment of electrons to gaseous anions (negatively charged molecules), inducing diagnostic fragmentation of the target molecule in a process termed negative ion electron capture dissociation (niECD). Adding electrons (which bear a negative charge) to anions (which also are negatively charged) is challenging, due to charge repulsion. Having developed this method, Dr. Hakansson is now working to improve our understanding and broaden the applicability and availability of niECD. The research is providing new approaches to biomolecular structural characterization with important implications for drug discovery and enhanced understanding of the molecular basis of living organisms. Students involved gain exposure to highly interdisciplinary research. Dr. Hakansson also works to bring appreciation for these concepts and for broader STEM opportunities to middle school students in an effort to boost interest in the scientific method at a young age. The Hakansson group is exploring novel niECD instrument configurations, including extension to matrix-assisted laser desorption/ionization and nano-electrospray ionization. They are working to implement niECD in a high pressure cell, enabling use with mass analyzers other than Fourier transform ion cyclotron resonance (FT-ICR). In pursuit of improved insight into the fundamental chemistry underlying niECD, they are pursuing two approaches (drift tube ion mobility and cross-sectional areas by FT-ICR, or CRAFTI (cross-sectional areas by FT-ICR) to testing Dr. Hakansson’s recent findings that compact, presumably salt-bridged structures are required for effective niECD of peptides. These efforts are supported by molecular modeling and density functional theory calculations, with a special focus on novel analyte classes such as carbohydrates and lipids, which were recently discovered by the Hakansson group to undergo niECD despite not fitting the previously proposed zwitterion mechanism.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.