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4000万人感染艾滋病毒/艾滋病；然而，保护性疫苗或有效的 尽管进行了40年的紧张研究，但治愈方法仍然难以捉摸。HIV-1通过其自身的功能逃避免疫系统 在感染和复制过程中的快速结构演变，以及这些结构变化在 HIV-1包膜蛋白(Env)对HIV-1融合和进入细胞的影响尚不完全清楚。我们的总目标是 在这个项目中定义了导致HIV-1的所谓前发夹中间体形成的步骤 环境将其腐烂成后来的聚变中间体。这一事件的发生通常被描述为一种类似鱼叉的行为 将FP插入到宿主膜中。虽然这一描述是对最早的锚定事件的说明，但它 不是身体描述性的。前发夹中间体的内在不稳定性使得观察到 它的结构很难处理。在这个项目中，我们的目标是将分子模拟的进展与尖端技术相结合 以高空间和时间分辨率询问这一过程的实验方法。要实现这些目标 AIMS，项目1将利用结构生物学和计算生物学核心的专业知识来开发和 用方法来解决这个问题。 我们的长期目标是开发一个完整的、时间分辨的和原子详细的HIV-1环境机制 核聚变。该项目的总体目标是开发和应用计算和结构方面的新方法 生物学使得在融合过程中询问罕见的瞬时状态成为可能。具体目标 在这项建议中是：(I)确定引发融合肽从其 与环境三聚体结合，(Ii)检查融合肽从其三聚体锚定到宿主的通道 膜表面，(Iii)鉴定融合肽插入、组装和锚定的决定因素 宿主膜，以及iv)描述促进gp120从gp41脱落的构象转变。这个 推动这项研究的中心假设是，每一次转变都受到严格的监管，表现出顺序的、合作的 在每个阶段进行控制。这个项目的基本原理是对这一过程进行先进的多尺度建模 与尖端的结构生物学工具相结合，可以解释这种转变的机制 对进入的中间阶段进行了规定。 在完成这些目标后，我们期望提供动力学解析的、原子级别的动力学理解 HIV-1 Env融合多肽的触发、释放和膜结合。这些成果将具有广泛的应用前景 特别是对艾滋病毒-1疫苗和药物开发的影响，以及对一般病毒进入调查的影响。