Enabling ion Mobility Spectrometry/Mass Spectrometry Methods to Study Conformational Dynamics of Protein Systems

在化学系化学测量和成像项目的支持下，佛罗里达州立大学的Christian Bleihold和他的研究小组正在开发新的方法来表征蛋白质的结构动力学，这些蛋白质在生物细胞内发生的化学反应中起着关键作用。这些新方法将联合收割机与计算化学方法相结合，增强串联离子迁移谱与质谱联用的能力。由于这些方法可以提供与正常和异常细胞生物学相关的化学方面的新知识，因此它们可以提供对细胞功能和细胞功能障碍的新见解，这可能是一种相关的新工具，可以深入了解疾病的演变。将通过与学术界和工业界合作者的互动，以及通过网站和讲习班向潜在用户广泛传播想法和成果（包括软件工具），加强影响。从事该项目的学生将接受仪器，计算方法，生物化学和复杂数据分析方面的培训。蛋白质的动力学性质极大地促进了蛋白质的化学反应。然而，在复杂样品或异质蛋白质系统的背景下研究蛋白质运动是具有挑战性的。离子迁移谱与质谱联用（IMS/MS）方法非常适合于处理由蛋白质型的存在引起的复杂性，并能够系统地测量蛋白质组，但存在两个主要缺点：（1）仍然不清楚在没有溶剂的情况下溶液相蛋白质运动的哪些方面被保留;和（2）根据蛋白质结构从其测量的取向平均碰撞截面明确地解释IMS/MS谱是具有挑战性的。Bleiholder博士和他的团队将描述在没有溶剂的情况下，配体和非配体蛋白质系统的溶液相运动的哪些方面被保留。这一目标是通过实验串联捕获IMS/MS（串联TIMS/MS）和计算结构弛豫近似（SRA）的方法，最近在Bleiholder laboratory.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Christian Bleiholder and his research group at Florida State University are developing new approaches to characterize the structural dynamics of proteins that play critical roles in chemical reactions occurring within biological cells. These new approaches will combine and enhance the capabilities of tandem-ion mobility spectrometry coupled with mass spectrometry in conjunction with computational chemistry methods. Because these approaches can provide new knowledge on the chemistry associated with both normal and abnormal cell biology, they may offer novel insight into the functioning of cells and cell dysfunction, potentially a relevant new tool to provide insight into the evolution of disease. Impact will be enhanced through interactions with academic and industrial collaborators, and by broad dissemination of ideas and results (including software tools) to potential users through websites and workshops. Students working on the project will be trained in instrumentation, computational methods, biochemistry, and analysis of complex data. The dynamic nature of proteins contributes greatly to the chemical reactions of proteins. However, protein motions are challenging to study in the context of complex samples or heterogenous protein systems. Ion mobility spectrometry methods coupled with mass spectrometry (IMS/MS) are well-suited to handle the complexity arising from presence of proteoforms and enable systematic measurements of proteomes, but suffer from two major shortcomings: (1) It remains unclear which aspects of the solution phase protein motions are retained in the absence of solvent; and (2) it is challenging to unambiguously interpret IMS/MS spectra in terms of protein structures from their measured orientationally-averaged collision cross sections. Dr. Bleiholder and his team will characterize which aspects of solution phase motions of liganded and unliganded protein systems are retained in the absence of solvent. This objective is to be accomplished by means of the experimental tandem-trapped IMS/MS (tandem-TIMS/MS) and the computational Structure Relaxation Approximation (SRA) methods recently developed in the Bleiholder laboratory.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.