Integrated tools for higher order structure determination by cross-link analysis

通过交联分析确定高阶结构的集成工具

基本信息

批准号：
9347159
负责人：
Beatrix Magdalena Ueberheide
金额：
$ 22.49万
依托单位：
PROTEIN METRICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347159
关键词：
Address Adopted Adoption Affinity Algorithmic Software Algorithms Amination Amines Antibodies Antigen-Antibody Complex Antigens Area Benchmarking Biological Biological Products Biology CCNE1 gene Carboxylic Acids Cell Membrane Permeability Chemicals Chemistry Complex Computer software Crosslinker Cullin Proteins DNA-Directed RNA Polymerase Data Data Set Deuterium Development Epitopes Escherichia coli Glycopeptides Goals Health Higher Order Chromatin Structure Histone H3 Human Hydrogen In Vitro Individual Industrialization Industry Ions Laboratories Length Lysine Maps Mass Spectrum Analysis Medical Research Methods Modification Peptides Pharmaceutical Preparations Phase Protein-Protein Interaction Map Proteins Proteomics Reagent Research Sales Sampling Sensitivity and Specificity Small Business Technology Transfer Research Solvents Standardization Structure Techniques Testing Time Training Visualization software Water blind crosslink data acquisition drug development improved in vivo instrumentation novel protein complex protein protein interaction search engine therapeutic protein three dimensional structure tool translational medicine vaccine development

Address Adopted Adoption Affinity Algorithmic Software Algorithms Amination Amines Antibodies Antigen-Antibody Complex Antigens Area Benchmarking Biological Biological Products Biology CCNE1 gene Carboxylic Acids Cell Membrane Permeability Chemicals Chemistry Complex Computer software Crosslinker Cullin Proteins DNA-Directed RNA Polymerase Data Data Set Deuterium Development Epitopes Escherichia coli Glycopeptides Goals Health Higher Order Chromatin Structure Histone H3 Human Hydrogen In Vitro Individual Industrialization Industry Ions Laboratories Length Lysine Maps Mass Spectrum Analysis Medical Research Methods Modification Peptides Pharmaceutical Preparations Phase Protein-Protein Interaction Map Proteins Proteomics Reagent Research Sales Sampling Sensitivity and Specificity Small Business Technology Transfer Research Solvents Standardization Structure Techniques Testing Time Training Visualization software Water blind crosslink data acquisition drug development improved in vivo instrumentation novel protein complex protein protein interaction search engine therapeutic protein three dimensional structure tool translational medicine vaccine development

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项目摘要

Summary The use of mass spectrometry (MS) for quantitative protein characterization has increased dramatically; identifying and quantifying thousands of proteins is no longer a heroic task nor is characterizing therapeutic proteins in detail. Due to widely available software, quantitative mass spectrometry has become routine and widely used for addressing questions in basic biology, translational medicine and drug development. MS Methods are now poised to have similar impact on the study of protein-protein interaction and higher order structure (HOS) determination. In particular, crosslinking mass spectrometry, which obtains distance and accessibility constraints from two-ended chemical modifications, is emerging as a powerful tool to map protein-protein interaction interfaces. Recent years have seen large improvements in crosslink mass spectrometry. Yet despite these advances, crosslink analysis is not yet a technique that has found widespread use, due to a range of problems such as the low abundance of crosslinked peptides, unavailability of proprietary reagents, the need for different search algorithms adopted to specific cross-linkers, and the difficulty of reliably characterizing crosslinked peptide spectra. To alleviate these problems and democratize the use of crosslinking, we propose to develop standardized and effective methods for crosslinking in conjunction with sensitive and accurate search algorithms, incorporated into our well-established Byonic search engine. Our algorithms will support almost all commercially available crosslinking chemistries and most major peptide fragmentation methods (ETD, CAD/HCD, EthcD), as well as cleavable and non-cleavable crosslinkers. The near universal applicability and ease-of-use of the software will promote rapid adoption of crosslinking mass spectrometry in academic research and biopharmaceutical development.

概括使用质谱（MS）来定量蛋白质表征增加了急剧识别和量化数千种蛋白质不再是英勇的任务，也不是详细表征治疗蛋白。由于广泛可用的软件，定量质量光谱法已成为常规，并广泛用于解决基本生物学中的问题，翻译医学和药物开发。 MS方法现在已经准备好具有类似的对蛋白质蛋白质相互作用和高阶结构（HOS）的研究的影响决心。特别是交联质谱，可获得距离和可及性从两端化学修改中的约束，正在成为绘制的强大工具蛋白质 - 蛋白质相互作用界面。近年来，交叉链接有很大改善质谱法。尽管有这些进展，但交联分析还不是一种技术由于多种问题，诸如低丰度交联的肽，专有试剂的不可用，需要不同的搜索采用了特定交联的算法，以及可靠表征的难度交联的肽光谱。为了减轻这些问题并使使用交联的使用民主化，我们建议开发标准化和有效的方法与敏感和准确的交联方法搜索算法，并入我们良好的Byonic搜索引擎中。我们的算法将支持几乎所有商业上可用的交联化学和大多数主要的肽碎裂方法（ETD，CAD/HCD，ETHCD），以及可裂解和不可裂解的交联。该软件的几乎普遍适用性和易用性将促进快速在学术研究和生物制药中采用交联质谱发展。