Project 1 - Molecular Dynamics of HIV-1 Entry: Visualizing Transient Intermediates

项目 1 - HIV-1 进入的分子动力学：可视化瞬时中间体

• 批准号: 10643917
• 负责人: Rory Henderson
• 金额: $ 25.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643917
• 关键词: Acceleration; Automobile Driving; Bioinformatics; Biophysics; Cells; Complex; Computational Biology; Coupled; Coupling; Cryoelectron Microscopy; Elements; Ensure; Event; Evolution; Goals; HIV; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; HIV/AIDS; Hydrophobicity; Immune Evasion; Immune system; Infection; Investigation; Kinetics; Location; Mediating; Membrane; Methods; Molecular; Molecular Conformation; Movement; Mutation; Pathway interactions; Peptides; Persons; Positioning Attribute; Process; Proteins; Publishing; Research; Resolution; Roentgen Rays; Sampling; Site; Structure; Surface; Thermodynamics; Time; Tryptophan; Vaccines; Virus; Visualization; base; conformational conversion; design; drug development; expectation; experimental study; extracellular vesicles; molecular dynamics; multi-scale modeling; novel; prevent; receptor; simulation; structural biology; temperature jump; temporal measurement; tool; vaccine development

Abstract – Project 1 Approximately 40 million people worldwide are living with HIV/AIDS; however, a protective vaccine or functional cure remain elusive despite four decades of intense research. HIV-1 evades the immune system through its rapid structural evolution during infection and replication, and the implications of these structural changes in the HIV-1 Envelope (Env) protein on HIV-1 fusion and entry into cells is not completely understood. Our overall goal in this project is to define the steps leading to formation of the so called pre-hairpin intermediate of the HIV-1 Env to its decay into later fusion intermediates. Initiation of this event is typically described as a ‘harpoon-like” insertion of the FP into the host membrane. While this depiction is illustrative of the earliest anchoring event, it is not physically descriptive. The inherent instability of the pre-hairpin intermediate has rendered observation of its structure intractable. In this project, we aim to combine advances in molecular simulation with cutting-edge experimental methods to interrogate this process at high spatial and temporal resolution. To accomplish these aims, Project 1 will leverage expertise in the structural biology and computational biology cores to develop and apply methods to this problem. Our long-term goal is to develop a complete, time resolved and atomically detailed mechanism of HIV-1 Env fusion. The overall objective for this project is to develop and apply new methods in computational and structural biology to make possible the interrogation of rare transient states along the fusion pathway. The specific targets in this proposal are (i) to determine the conformational transitions that trigger fusion peptide release from its association with the Env trimer, (ii) to examine passage of the fusion peptide from its trimeric anchor to the host membrane surface, (iii) to identify the determinants of fusion peptide insertion, assembly, and anchoring in the host membrane, and iv) to delineate the conformational transitions that facilitate gp120 shedding from gp41. The central hypothesis driving this study is that each transition is tightly regulated, displaying sequential, cooperative control at each stage. The rationale for this project is that advanced, multiscale modelling of this process combined with cutting edge structural biology tools can elucidate the mechanism by which transitions at this intermediate stage of entry are regulated. Upon completion of these aims, we expect to provide kinetically resolved, atomic-level dynamics understanding of HIV-1 Env fusion peptide triggering, release, and membrane engagement. These results will have broad impact on HIV-1 vaccine and drug development specifically and on virus entry investigations generally.

摘要 - 项目1 全世界约有4000万人患有艾滋病毒/艾滋病；但是，受保护的疫苗或功能 治愈仍然是难以捉摸的任务四十年的深入研究。 HIV-1通过其逃避免疫系统 感染和复制过程中的结构发展以及这些结构变化在 HIV-1包膜（ENV）蛋白在HIV-1融合和进入细胞中的蛋白质尚未完全了解。我们的总体目标 在这个项目中，定义了导致形成所谓的HIV-1中级中级的步骤 env腐烂到后来的融合中间体。这个事件的启动通常被描述为“鱼叉状” 将FP插入宿主膜。尽管此描述是最早的锚定事件的说明，但 没有物理描述性。发发前中级的固有不稳定已使观察到 它的结构棘手。在这个项目中，我们旨在将分子模拟的进步与前沿结合起来 在高空间和临时分辨率下询问此过程的实验方法。完成这些 目的，项目1将利用结构生物学和计算生物学核心方面的专业知识来发展和 将方法应用于此问题。 我们的长期目标是开发HIV-1 Env的完整，时间解决和原子详细的机制 融合。该项目的总体目标是在计算和结构中开发和应用新方法 生物学使沿融合途径对稀有瞬态状态的审问。特定目标 在此提案中，（i）确定触发融合肽从其中释放的构象转变 与Env Trimer的关联，（ii）检查融合肽从三聚锚的通过到宿主的通过 膜表面，（iii）识别融合肽插入，组装和锚定的决定剂 宿主膜和iv）描绘了促进GP120脱离GP41的构象转变。这 驱动这项研究的中心假设是每个过渡都受到严格的调节，显示顺序，合作 在每个阶段控制。该项目的理由是该过程的先进的多尺度建模 结合前沿结构生物学工具可以阐明过渡的机制 中间阶段受到调节。 完成这些目标后，我们希望提供动力学解决的原子级动力学理解 HIV-1环境融合肽的触发，释放和膜的参与。这些结果将广泛 一般对HIV-1疫苗和药物开发的影响，通常对病毒进入研究。