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Next-Generation Collision Induced Unfolding Analysis of Proteins

下一代蛋白质碰撞诱导解折叠分析

基本信息

批准号：
1808541
负责人：
Brandon Ruotolo
金额：
$ 33万
依托单位：
Regents of the University of Michigan - Ann Arbor
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808541&HistoricalAwards=false
关键词：
Next Generation Collision Induced Unfolding

项目摘要

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, and with partial co-funding from the Division of Molecular and Cellular Biosciences, Professor Brandon Ruotolo and his group at the University of Michigan are developing powerful new tools for characterizing the 3-dimensional structure of proteins - key molecules in life processes. Specifically, the Ruotolo group is expanding the capabilities of "collision induced unfolding" (CIU), an approach which studies protein structures by quickly removing the water which surrounds protein molecules in their normal environment, then induces their unfolding while monitoring their size and shape using a state-of-the-art tool known as ion mobility-mass spectrometry (IM-MS). The approach has the potential to revolutionize the detail and acquisition speed with which protein stability can be evaluated. Potential applications include the rapid analysis of biotherapeutic proteins and their mode of operation. The work provides excellent training for students interested in research at the interface between chemical measurements and the pharmaceutical sciences.The research addresses three main goals: (1) creating a complete physical description of factors impacting the peak width for traveling-wave-type ion mobility separators, and validating the resulting predictions against standards; (2) developing next-generation software that incorporates the interpretation of IM peak width into CIU analysis workflows in the form of highly-parameterized multi-modal Gaussian fitting in both two and three dimensions; and (3) creating parallelized, multi-dimensional CIU methods capable of rapidly tracking the unfolding patterns of protein mixtures across many charge states simultaneously, even in the presence of significant chemical noise. The new CIU tools are being tested using therapeutic proteins of significance to the biotechnology sector.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.

在化学系化学测量和成像项目的支持下，以及分子和细胞生物科学系的部分共同资助下，密歇根大学的布兰登·鲁托洛教授和他的团队正在开发强大的新工具，用于表征蛋白质的三维结构-生命过程中的关键分子。具体来说，Ruotolo小组正在扩展“碰撞诱导解折叠”（CIU）的能力，这是一种通过快速去除正常环境中蛋白质分子周围的水来研究蛋白质结构的方法，然后诱导它们的解折叠，同时使用最先进的工具离子迁移率质谱（IM-MS）监测它们的大小和形状。该方法有可能彻底改变蛋白质稳定性评估的细节和采集速度。潜在的应用包括快速分析生物蛋白质及其操作模式。这项工作为那些对化学测量和制药科学之间的接口研究感兴趣的学生提供了很好的培训。这项研究有三个主要目标：（1）建立一个完整的物理描述，描述影响行波型离子迁移率分离器峰宽的因素，并根据标准验证所得到的预测结果;（2）开发下一代软件，该软件以二维和三维的高度参数化多模态高斯拟合的形式将IM峰宽的解释并入CIU分析工作流程中;以及（3）创建并行化的、多维的CIU方法，该方法能够同时快速跟踪跨许多电荷状态的蛋白质混合物的解折叠模式，即使在存在显著的化学噪声的情况下。该奖项反映了NSF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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Semi-Empirical Framework for Interpreting Traveling Wave Ion Mobility Arrival Time Distributions

DOI：
10.1007/s13361-019-02133-6
发表时间：
2019-06-01
期刊：
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
影响因子：
3.2
作者：
Dixit, Sugyan M.;Ruotolo, Brandon T.
通讯作者：
Ruotolo, Brandon T.

CIUSuite 2: Next-Generation Software for the Analysis of Gas-Phase Protein Unfolding Data

DOI：
10.1021/acs.analchem.8b05762
发表时间：
2019-02-19
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
Polasky, Daniel A.;Dixit, Sugyan M.;Ruotolo, Brandon T.
通讯作者：
Ruotolo, Brandon T.

An Improved Calibration Approach for Traveling Wave Ion Mobility Spectrometry: Robust, High-Precision Collision Cross Sections

DOI：
10.1021/acs.analchem.0c04948
发表时间：
2021-02-23
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
Richardson, K.;Langridge, D.;Ruotolo, B. T.
通讯作者：
Ruotolo, B. T.

Quantitative collision‐induced unfolding differentiates model antibody–drug conjugates

定量碰撞诱导的解折叠区分模型抗体药物缀合物

DOI：
10.1002/pro.3560
发表时间：
2018
期刊：
Protein Science
影响因子：
8
作者：
Tian, Yuwei;Lippens, Jennifer L.;Netirojjanakul, Chawita;Campuzano, Iain D. G.;Ruotolo, Brandon T.
通讯作者：
Ruotolo, Brandon T.

A Novel Ion Pseudo-trapping Phenomenon within Traveling Wave Ion Guides