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Algorithms and Software for Protein-Family De Novo Sequencing

蛋白质家族从头测序的算法和软件

基本信息

批准号：
8119094
负责人：
MARSHALL Wayne BERN
金额：
$ 25.15万
依托单位：
PALO ALTO RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119094
关键词：
Algorithms Amino Acid Sequence Analgesics Antibodies Archives Attention Award Charge Complex Mixtures Computer software Conotoxin Contracts Cysteine Data Data Analyses Databases Disease Dissociation Electron Transport FDA approved Generations Government HIV HIV Infections HIV Seropositivity Human Ion Channel Ions Knowledge Laboratories Length Libraries Marshal Mass Spectrum Analysis Measures Methods Mutation Organism Patients Pattern Peptides Performance Pharmacologic Substance Positioning Attribute Principal Investigator Protein Databases Protein Family Proteins Proteomics Public Health Research Sampling Serum Snails Source Speed Spiders Techniques Toxin Universities Viral Load result Work alpha-Conotoxin base data acquisition improved interest neutralizing antibody polyclonal antibody programs protein aminoacid sequence public health relevance success tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed project is to enable mass-spectrometry-based protein research. The project will develop algorithms and software for de novo peptide sequencing by tandem mass spectrometry, taking advantage of two currently unexploited information channels: protein family homology, and multiple complementary spectra of the same peptide. Homology will allow the de novo sequencing program to limit attention to peptides fitting certain motifs or constraints. With strict constraints, the program would search only the most likely mutations of known sequences, but with loose constraints the program would search as widely as current de novo sequencing programs. Complementary spectra, for example, one CID (collision-induced dissociation) and one ETD (electron-transfer dissociation) spectrum, give more complete fragmentation, and more importantly, help the program recognize which peaks correspond to which ion types, for example, helping to distinguish b-ions from y-ions. New software produced by the project will be put to immediate use in sequencing antibodies and toxins. The specific aims of the project are: homology-guided generation of candidate peptides, utilization of multiple and complementary spectra (for both candidate generation and scoring), and application and deployment of the software for sequencing polyclonal serum antibodies and complex mixtures of snail and spider toxins. These are high-value targets because the antibodies are reactive to HIV, and the toxins are valuable both as probes to study ion channels and also as pharmaceutical leads. If the project achieves its aims, exact sequencing of unknown peptides will become much easier than it is today, laboratories worldwide will take advantage of the new data acquisition and analysis strategies, and biomedical discovery will be greatly accelerated. PUBLIC HEALTH RELEVANCE: The proposed project is important to public health because it will enable exact identification of unknown, unsequenced proteins, including spider and snail toxins and polyclonal antibodies captured from human serum. Snail toxins are already the basis for FDA-approved analgesics. Captured antibodies could enable antibody treatments for HIV infection and other diseases. .

描述（由申请人提供）：拟议项目的广泛、长期目标是实现基于质谱的蛋白质研究。该项目将开发通过串联质谱进行从头肽测序的算法和软件，利用两个目前未开发的信息通道：蛋白质家族同源性和同一肽的多个互补光谱。同源性将允许从头测序程序将注意力限制在适合某些基序或约束的肽上。在严格的约束下，该程序将仅搜索已知序列中最有可能的突变，但在宽松的约束下，该程序将与当前的从头测序程序一样广泛地搜索。互补光谱，例如，一种 CID（碰撞诱导解离）和一种 ETD（电子转移解离）光谱，可提供更完整的碎裂，更重要的是，帮助程序识别哪些峰对应于哪些离子类型，例如，帮助区分 b 离子和 y 离子。该项目开发的新软件将立即用于抗体和毒素的测序。该项目的具体目标是：同源引导候选肽的生成、利用多重互补光谱（用于候选肽生成和评分）以及应用和部署用于对多克隆血清抗体以及蜗牛和蜘蛛毒素的复杂混合物进行测序的软件。这些都是高价值的靶标，因为这些抗体对 HIV 具有反应性，而这些毒素既可以作为研究离子通道的探针，也可以作为药物先导化合物。如果该项目实现其目标，未知肽的精确测序将变得比今天容易得多，世界各地的实验室将利用新的数据采集和分析策略，生物医学发现将大大加速。公共健康相关性：拟议的项目对公共健康很重要，因为它将能够准确识别未知的、未测序的蛋白质，包括蜘蛛和蜗牛毒素以及从人血清中捕获的多克隆抗体。蜗牛毒素已经成为 FDA 批准的镇痛药的基础。捕获的抗体可以用于治疗艾滋病毒感染和其他疾病。。