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: 10458681
• 负责人: Rory Henderson
• 金额: $ 47.69万
• 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/10458681
• 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.

抽象的 大分子相互作用通常从束缚态的角度理解为 通过 X 射线晶体学或动力学冷冻电子显微镜以高分辨率测定 和用于描述相互作用过程的热力学参数。这种做法是， 然而，在空间和时间上仅限于对该过程的大量人口水平描述 从亲和力和动力学的角度，以及束缚态的单态角度 结构。事实上，形成相互作用的过程是相当复杂的，涉及随机的 分子之间的碰撞，通过一系列复杂的途径过渡到最终的 束缚态。这些碰撞以及它们实现束缚态的机制 确定关联率，但当前方法尚未明确定义。这里，综合了 询问抗体过程的计算和实验方法 HIV-1 N332-聚糖中的抗原结合广泛靶向中和抗体 能够精确增强抗体-免疫原结合率动力学。使用分子 模拟，将在原子上阐明对束缚状态转换机制的全面遭遇 解决。这项工作的目标是能够精确选择具有亲和力的抗原 梯度有利于通过一致诱导广泛中和抗体反应 疫苗接种。交互动力学的设计原则的定义 在蛋白质工程背景下进行操作将对新颖的设计产生广泛的影响 任何生物学背景下的治疗方法和大分子探针。