权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Computational design of specific binding proteins using Leave-One-Out

使用留一法进行特异性结合蛋白的计算设计

基本信息

批准号：
8928499
负责人：
CHRISTOPHER BYSTROFF
金额：
$ 31.66万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8928499
关键词：
Address Affinity Algorithm Design Algorithms Amino Acid Sequence Amino Acid Substitution Anthrax disease Appearance Authorization documentation Avian Influenza Binding Binding Proteins Biological Markers Biosensor Complement Computing Methodologies DNA Shuffling Dengue Virus Detection Development Diagnostic Disease Disulfides Elements Engineering Event Feedback Fluorescence Fluorescent Probes Foot-and-Mouth Disease Funding Genes Goals Green Fluorescent Proteins HIV In Vitro Individual Influenza A Virus, H5N1 Subtype Influenza Hemagglutinin Left Libraries Ligand Binding Memory Modification Monoclonal Antibodies Occupations Online Systems Pathway interactions Patient Self-Report Peptides Property Proteins Proteomics Protocols documentation Reporting Research Research Design Running Shapes Signal Transduction Site Specific qualifier value Specificity Speed Structure System Therapeutic Thermodynamics Time United States National Institutes of Health Validation Viral Proteins Work base cancer cell cluster computing cost design enzyme activity global health improved in vivo influenzavirus interest methicillin resistant Staphylococcus aureus microorganism new technology novel novel strategies parallel computer pathogen protein folding protein purification protein structure public health relevance rapid detection receptor sensor software development therapeutic protein yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Computational design of specific binding proteins using Leave-One-Out The goal of this research is to be able to design a receptor protein for any protein target. Furthermore, we propose that the binding event will be signaled by the appearance of enzyme activity or fluorescence. The novel binding proteins will be able to sense and report the presence of a specific protein or peptide in a mixture of others, allowing the detection of disease agents or other proteins of interest both in vivo and in vitro. The new approach takes advantage of protein folding pathways. When proteins fold, they do so in a specified order of events, and the events can be predicted based on the structure of the protein. When a protein finishes folding, its activity is immediately turned on. If we leave out one small piece of the protein so that the folding cannot finish, then the protein sits in an inactive state ntil the missing piece appears. Using this Leave-One- Out strategy, partially folded proteins become sensors for their missing pieces. Using computational design algorithms, a new amino acid sequence can be substituted for the left out piece. This new sequence can be from anthrax, avian flu, a cancer cell marker or any other protein. Computational substitution of the amino acids surrounding this new sequence is made possible using massively parallel computing clusters and grid computing, and by dividing the design task into numerous smaller tasks based on what is known about protein folding and energy calculations. The final design is a protein that wraps around the target peptide, specifically identifying it by its complementary shape. Green fluorescent protein has been the subject of the first leave-one-out design studies and has yielded specific binding proteins that glow only when the target peptide is present.

描述（由申请人提供）：使用留一法的特异性结合蛋白的计算设计本研究的目标是能够为任何蛋白质靶标设计受体蛋白。此外，我们提出，结合事件将通过酶活性或荧光的出现来发出信号。新的结合蛋白将能够感测和报告特定蛋白质或肽在其它蛋白质或肽的混合物中的存在，从而允许在体内和体外检测疾病因子或其它感兴趣的蛋白质。新方法利用了蛋白质折叠途径。当蛋白质折叠时，它们以特定的事件顺序进行折叠，并且可以基于蛋白质的结构来预测事件。当一个蛋白质完成折叠时，它的活性立即被激活。如果我们遗漏了一小块蛋白质，折叠就不能完成，那么蛋白质就会处于非活性状态，直到缺失的那块蛋白质出现。使用这种留一策略，部分折叠的蛋白质成为其缺失片段的传感器。使用计算设计算法，可以用新的氨基酸序列取代遗漏的片段。这个新序列可以来自炭疽、禽流感、癌细胞标记或任何其他蛋白质。使用大规模并行计算集群和网格计算，并根据已知的蛋白质折叠和能量计算，将设计任务划分为许多较小的任务，使围绕这个新序列的氨基酸的计算取代成为可能。最终的设计是一种蛋白质，它包裹在目标肽周围，通过其互补的形状特异性地识别它。绿色荧光蛋白已经成为第一个留一法设计研究的主题，并且已经产生了仅当靶肽存在时才发光的特异性结合蛋白。