Prediction of the Structure of Therapeutic Antibodies with their Antigens

治疗性抗体及其抗原结构的预测

• 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
• 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

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.

治疗性抗体结构及其抗原的预测 项目概要 抗体对于识别外来入侵者起着至关重要的作用。由于其高亲和力和特异性，它们 已被用作治疗分子和用于传感和组装的生物技术组件。 最近的高通量测序和纳米流体技术已经阐明了大量 (103–104) 天然和抗原暴露的抗体序列，现在可以确定一套完整的病毒 一个人根据自己的抗体遇到过的情况。除了生物学、医学和 技术重要性，关于抗体的广泛知识使它们成为理想的模型系统 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充分释放丰富蛋白质的缺失环节 抗体和抗原库中的信息。先前的工作证明在预测抗体方面取得了成功 结构，该提案重点关注对接问题。虽然对接算法对于本地来说是可靠的 搜索和小的构象变化，在寻找大抗原以 识别表位并在存在骨架灵活性或确定正确的结合方向时 同源建模起始结构的不确定性。考虑结合引起的骨干 构象变化仍然是蛋白质-蛋白质对接领域的中心难点，主要是由于 抽样限制。另一个挑战是许多病毒外壳和细菌蛋白都是糖基化的。 聚糖具有良好的水合性并且具有柔韧性；这些修改通常会被对接完全忽略 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，使其可用于解码生物机制和设计改进的治疗方法。 因此，当前项目的前两个目标是（1）开发快速、积极、灵活的骨干对接 方法，以及（2）扩展对接以包括糖基化抗原。最后，第三个目标是（3）申请 抗体建模和对接以确定乳糜泻和肺部疾病的生物标志物和治疗方法 高血压。

项目成果

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

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

• DOI: 10.1002/prot.25402
• 发表时间: 2018-01
• 期刊: Proteins
• 影响因子: 2.9
• 作者: Koehler Leman J;D'Avino AR;Bhatnagar Y;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
• 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

Development and Evaluation of GlycanDock: A Protein-Glycoligand Docking Refinement Algorithm in Rosetta.

• DOI: 10.1021/acs.jpcb.1c00910
• 发表时间: 2021-06-16
• 期刊: The journal of physical chemistry. B
• 作者: Nance ML;Labonte JW;Adolf-Bryfogle J;Gray JJ
• 通讯作者: Gray JJ

Analysis and modeling of the variable region of camelid single-domain antibodies.

• DOI: 10.4049/jimmunol.1100116
• 发表时间: 2011-06-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Sircar A;Sanni KA;Shi J;Gray JJ
• 通讯作者: Gray JJ