Assessing HIV-1 Broadly Neutralizing Antibody Association Pathways for Vaccine Immunogen Design

评估疫苗免疫原设计的 HIV-1 广泛中和抗体关联途径

• 批准号: 10295287
• 负责人: Rory Henderson
• 金额: $ 46.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295287
• 关键词: Affinity; Antibodies; Antibody Response; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Binding Sites; Biological; Cell Lineage; Complex; Cryoelectron Microscopy; Data; Development; Disease; Dissociation; Distant; Ensure; Equation; Failure; Goals; HIV-1; Immunization; Kinetics; Knock-out; Life; Measures; Methods; Molecular; Mutagenesis; Mutate; Mutation; Outcome; Pathway interactions; Physics; Play; Polysaccharides; Population; Process; Protein Engineering; Resolution; Role; Series; Site; Structure; Thermodynamics; Time; Vaccination; Vaccine Design; Vaccines; Vertebral column; X-Ray Crystallography; antigen antibody binding; base; design; disorder prevention; env Gene Products; molecular dynamics; neutralizing antibody; novel; novel strategies; novel therapeutics; preference; protein structure; response; simulation; tool

ABSTRACT Macromolecular interactions are often understood from the perspective of the bound state as determined at high-resolution from x-ray crystallography or cryo-electron microscopy with kinetic and thermodynamic parameters used to describe the interaction process. This approach is, however, limited spatially and temporally to a bulk, population level description of the process from the perspective of affinity and kinetics, and the single state perspective of a bound state structure. The process of forming an interaction is, in fact, quite complex, involving random collisions between molecules that transition through a complicated set of pathways to the final bound state. These collisions and the mechanism by which they achieve the bound state determine the association rate but are not well defined by current methods. Here, a combined computational and experimental approach to the interrogation of the process of antibody- antigen binding in HIV-1 N332-glycan targeting broadly neutralizing antibodies is proposed to enable precise enhancement of antibody-immunogen association rate kinetics. Using molecular simulation, full encounter to bound state transition mechanisms will be elucidated at atomic resolution. The goal of this effort is to enable precise selection of antigens with an affinity gradient conducive to the consistent induction of broadly neutralizing antibody responses via vaccination. The definition of design principles by which the kinetics of an interaction may be manipulated in a protein engineering context will have a broad impact on the design of novel therapeutics and macromolecular probes in any biological context.

摘要 大分子相互作用通常从束缚态的角度理解为 在高分辨率下从x射线结晶学或冷冻电子显微镜确定的动力学 以及用于描述相互作用过程的热力学参数。这种方法是， 然而，在空间和时间上受限于对这一过程的大量、人口层面的描述 从亲和力和动力学的角度，以及束缚态的单态观点 结构。事实上，形成相互作用的过程是相当复杂的，涉及随机 分子之间的碰撞，通过一系列复杂的路径过渡到最终 束缚状态。这些碰撞以及它们达到束缚状态的机制 确定关联率，但目前的方法没有很好地定义。在这里，一个合并的 抗体形成过程的计算和实验研究方法 针对广谱中和抗体的HIV-1N332-葡聚糖的抗原结合被提出 实现抗体-免疫原结合率动力学的精确增强。使用分子 模拟，完全相遇束缚态跃迁机制将在原子 决议。这项工作的目标是能够精确地选择具有亲和力的抗原。 有助于一致地诱导广谱中和抗体反应的梯度 接种疫苗。设计原则的定义，相互作用的动力学可以根据这些原则 在蛋白质工程的背景下操纵将对小说的设计产生广泛的影响 任何生物学背景下的治疗学和大分子探针。