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.

摘要 大分子相互作用通常从结合态的角度理解为 通过X射线晶体学或低温电子显微镜以高分辨率测定， 热力学参数用于描述相互作用过程。这种方法是， 然而，在空间上和时间上局限于对该过程的大量、总体水平的描述 从亲和力和动力学的角度，以及结合态的单态角度， 结构事实上，形成相互作用的过程是相当复杂的， 分子之间的碰撞，通过一系列复杂的途径， 束缚态这些碰撞以及它们达到束缚态的机制 确定关联率，但是当前的方法没有很好地定义。在这里，一个组合 计算和实验的方法来询问抗体的过程- 提出了HIV-1 N332-聚糖靶向广泛中和抗体的抗原结合， 能够精确增强抗体-免疫原结合速率动力学。使用分子 模拟，充分遇到束缚态过渡机制将阐明在原子 分辨率这项工作的目标是能够精确选择具有亲和力的抗原， 梯度有助于通过以下途径一致诱导广泛中和抗体应答： 预防针设计原则的定义，通过这些原则，相互作用的动力学可能是 在蛋白质工程的背景下操纵将对新的蛋白质工程的设计产生广泛的影响。 治疗和大分子探针在任何生物学背景下。