Prediction of the Structure of Therapeutic Antibodies with their Antigens

治疗性抗体结构及其抗原的预测

• 批准号: 8546392
• 负责人: JEFFREY J GRAY
• 金额: $ 29.9万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546392
• 关键词: Address; Affinity; Age; Algorithms; Antibodies; Antibody Binding Sites; Antibody Repertoire; Antigen Targeting; Antigen-Antibody Complex; Antigens; Autoimmune Diseases; Benchmarking; Binding; Biological; Biological Models; Biological Phenomena; Bone Marrow; Charge; Complement component C1s; Complementarity Determining Regions; Complex; Data; Disease; Docking; Electrostatics; Enzymes; Epitopes; Food Hypersensitivity; Freedom; Genomics; Goals; Graft Rejection; Homology Modeling; Human; Immune system; Immunology; Individual; Inflammatory; Internet; Knowledge; Light; Maps; Medical; Methods; Modeling; Molecular Conformation; Movement; Mus; Mutation; Ovalbumin; Patients; Pharmaceutical Preparations; Plasma Cells; Play; Point Mutation; Positioning Attribute; Protein Binding; Proteins; Research; Resolution; Resources; Role; Sampling; Side; Specificity; Structural Models; Structure; System; Testing; Therapeutic; Therapeutic antibodies; Time; Transplantation; Uncertainty; Vaccines; Vertebral column; Work; antigen antibody binding; complement system; density; design; flexibility; food allergen; improved; insight; kinematics; molecular recognition; novel; polyclonal antibody; protein structure prediction; research study; statistics; therapeutic development; therapeutic target; three dimensional structure; vaccine development

DESCRIPTION (provided by applicant): Antibodies play a critical role in the immune system for recognition of foreign intruders. Because of their excellent affinity and specificity, they hav also been exploited as therapeutic molecules and biotechnological components for sensing and assembly. Structures of antibodies in complex with their antigens can yield insight into biological phenomena or drug and disease mechanisms. However, structures of antibodies and antibody-antigen complexes can be difficult, time consuming, and expensive to determine. The proposed research focuses on the computational prediction of the structure of antibodies and antibody-antigen complexes. Computational approaches are particularly important because the repertoire of antibodies in a human patient is far too large for complete structural characterization by experiment. Prior work has isolated the most critical challenges: most of the antibodies in the human repertoire have hypervariable CDR H3 loops longer than that which is predictable using current loop methods; backbone conformational uncertainty and flexibility confound current docking methods; and no current method can quantitatively predict antibody-antigen binding affinities from structure. Thus, the first three aims of the project are to (1) develop new methods to predict the structure of long CDR H3 loops using statistics to identify likely ¿ turns, (2) develop flexible backbone docking routines using an expanded ensemble approach with a conformational web, and (3) develop methods to quantitatively predict protein-protein binding affinity using improved electrostatics treatments. Finally, the fourth aim will be to (4) use existng and proposed methods to predict structures of antibodies and antibody-antigen complexes for entire polyclonal antibody repertoires. Structures will be predicted for antibody repertoires determined from bone marrow plasma cells of mice immunized against ovalbumin (a food allergen) and enzyme C1s (a therapeutic target for autoimmune diseases and transplant tolerance). Ultimately, these studies will yield insights into immunology, molecular recognition, and design of protein-protein interfaces and vaccines.

描述（由申请人提供）：抗体在免疫系统中起着识别外来入侵者的关键作用。由于其优异的亲和力和特异性，它们也被用作治疗分子和用于传感和组装的生物技术组件。抗体与抗原复合物的结构可以深入了解生物学