Prediction of the Structure of Therapeutic Antibodies with their Antigens

治疗性抗体及其抗原结构的预测

基本信息

批准号：
9923648
负责人：
JEFFREY J GRAY
金额：
$ 34.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923648
关键词：
Accounting Affinity Algorithms Antibodies Antigen Targeting Antigen-Antibody Complex Antigens Bacterial Proteins Binding Binding Proteins Biological Biological Markers Biological Models Biotechnology Capsid Proteins Carbohydrates Celiac Disease Chemistry Communities Complementarity Determining Regions Complex Computing Methodologies Consumption Cryoelectron Microscopy Crystallography Disease Docking Engineering Epitopes Gluten Glycoproteins Goals Heart Diseases High-Throughput Nucleotide Sequencing Homology Modeling Human Hydration status Immune System Diseases Immune system Individual Knowledge Link Lung diseases Measures Medical Methods Modeling Modification Molecular Conformation Motion Occupations Oligosaccharides Pathology Peptide/MHC Complex Play Polysaccharides Proteins Pulmonary Hypertension Research Resolution Role Sampling Scheme Scoring Method Serum Side Source Specificity Structural Models Structure Technology Testing Therapeutic Therapeutic antibodies Time Uncertainty Vertebral column Viral Virus Work base conformer flexibility improved innovation nanofluidic resistin success sugar three dimensional structure web app

项目摘要

Prediction of the Structure of Therapeutic Antibodies with their Antigens PROJECT SUMMARY Antibodies play a critical role for recognition of foreign intruders. Due to their high affinity and specificity, they have been exploited as therapeutic molecules and biotechnological components for sensing and assembly. Recent high-throughput sequencing and nanofluidics technologies have elucidated large sets (103–104) of naïve and antigen-exposed antibody sequences, and it is now possible to determine a complete set of viruses that an individual has encountered based on one’s antibodies. In addition to their biological, medical, and technological importance, the extensive knowledge about antibodies makes them an ideal model system for studying protein binding and recognition. A reliable toolkit to study protein binding and recognition is the missing link to fully unlock the bountiful information in antibody and antigen repertoires. Prior work demonstrated success in predicting antibody structures, and this proposal focuses on the docking problem. While docking algorithms are reliable for local searches and small conformational changes, significant challenges remain in searching large antigens to identify epitopes and in determining the correct binding orientation when there is backbone flexibility or uncertainty in the homology-modeled starting structures. Accounting for binding-induced backbone conformational changes remains the central difficulty in the protein–protein docking field, primarily due to sampling limitations. An additional challenge is that many viral coat and bacterial proteins are glycosylated. Glycans are well hydrated and can be flexible; these modifications are typically ignored entirely by docking algorithms. The long-term goal of this research is the accurate prediction of structures of antibodies and antibody–antigen complexes such that they are useful to decode biological mechanisms and engineer improved therapeutics. Thus, the first two aims of the current project are to (1) develop fast, aggressive, flexible backbone docking approaches, and (2) extend docking to include glycosylated antigens. Finally, the third aim will be to (3) apply antibody modeling and docking to determine biomarkers and therapeutics for celiac disease and pulmonary hypertension.

预测抗原治疗抗体的结构项目摘要抗体对于认识外国入侵者起着至关重要的作用。由于它们的高亲和力和特异性，他们已被探讨为用于敏感性和组装的治疗分子和生物技术成分。最近的高通量测序和纳米流体技术已经阐明了大型集合（103-104）幼稚和抗原暴露的抗体序列，现在可以确定一组完整的病毒一个人是根据一个人的抗体遇到的。除了它们的生物学，医疗和技术上的重要性，关于抗体的广泛知识使它们成为了理想的模型系统研究蛋白质结合和识别。研究蛋白质结合和识别的可靠工具包是完全解锁的缺失链接抗体和抗原库中的信息。先前的工作证明了在预测抗体方面的成功结构和该提案集中在对接问题上。停靠算法对本地可靠搜索和少量会议变化，在寻找大型抗原的挑战仍然存在确定表位并确定有骨架灵活性或同源模型的起始结构的不确定性。考虑绑定引起的骨干构象变化仍然是蛋白质 - 蛋白质对接场的中心难度，主要是由于采样限制。另一个挑战是，许多病毒外套和细菌蛋白都是糖基化的。聚糖水分充足，可以柔韧。这些修改通常完全通过对接而完全忽略算法。这项研究的长期目标是准确预测抗体和抗体 - 抗原的结构复合物使它们可用于解码生物学机制和工程师改进的治疗。这是当前项目的前两个目标是（1）快速，积极，灵活的骨干对接方法，（2）扩展对接以包括糖基化抗原。最后，第三个目标是（3）申请抗体建模和对接确定生物标志物和腹腔疾病的治疗高血压。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allosteric communication occurs via networks of tertiary and quaternary motions in proteins.

DOI：
10.1371/journal.pcbi.1000293
发表时间：
2009-02
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Daily MD;Gray JJ
通讯作者：
Gray JJ

Structure-based design of supercharged, highly thermoresistant antibodies.

DOI：
10.1016/j.chembiol.2012.01.018
发表时间：
2012-04-20
期刊：
Chemistry & biology
影响因子：
0
作者：
Miklos AE;Kluwe C;Der BS;Pai S;Sircar A;Hughes RA;Berrondo M;Xu J;Codrea V;Buckley PE;Calm AM;Welsh HS;Warner CR;Zacharko MA;Carney JP;Gray JJ;Georgiou G;Kuhlman B;Ellington AD
通讯作者：
Ellington AD

Comparison of NMR and crystal structures of membrane proteins and computational refinement to improve model quality.