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结合状态的角度理解为 用动力学从X射线晶体学或冷冻电子显微镜进行高分辨率确定 以及用于描述相互作用过程的热力学参数。这种方法是 但是，在空间和时间上限制了该过程的人口级别描述 从亲和力和动力学的角度来看 结构。实际上，形成互动的过程非常复杂，涉及随机 通过一组复杂的途径过渡到最终的分子之间的碰撞 约束状态。这些碰撞和实现约束状态的机制 确定关联率，但没有通过当前方法很好地定义。在这里，一个组合 计算和实验方法审问抗体过程 HIV-1 N332-Glycan靶向靶向广泛中和抗体的抗原结合被提出 可以精确增强抗体免疫原结合率动力学。使用分子 模拟，将在原子上阐明与状态过渡机制的完全相遇 解决。这项努力的目的是实现具有亲和力的精确选择抗原 梯度有利于通过 疫苗接种。互动动力学可能是设计原理的定义 在蛋白质工程环境中操纵将对新颖的设计产生广泛的影响 在任何生物学背景下的治疗剂和大分子探针。