Determining the molecular mechanisms of HIV-1 maturation

确定 HIV-1 成熟的分子机制

• 批准号: 10750083
• 负责人: Juan Roberto Perilla Jimenez
• 金额: $ 61.37万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750083
• 关键词: Adoption; Affect; Architecture; Binding; Biophysics; Capsid; Capsid Proteins; Cells; Collaborations; Communities; Computing Methodologies; Cryoelectron Microscopy; Diffusion; Equipment; Event; Experimental Designs; Grain; Guide RNA; HIV Budding; HIV-1; In Vitro; Membrane; Membrane Lipids; Methods; Modeling; Molecular; Molecular Conformation; Morphology; Motion; Nucleocapsid; Pathway interactions; Peptide Hydrolases; Peptides; Physical condensation; Process; Protein Engineering; Proteins; Proteolytic Processing; Research Personnel; Resolution; Resources; Retrovirology; Series; Shapes; Site; Structure; Testing; Thick; Thinness; Tomogram; Tubular formation; Validation; Viral; Viral Physiology; Virion; Virus; Work; biophysical properties; fluidity; gag Gene Products; in vivo; innovation; instrumentation; molecular dynamics; molecular scale; movie; mutant; particle; protein complex; simulation; supercomputer; tool; virtual reality

Project Abstract Before a newly budded HIV-1 particle becomes fusogenic (and infective) it must undergo maturation. During maturation the contents of the virion transform from a spherical shell into a conical structure after a series of cleavages of the 55 kDa Gag polyprotein by the viral protease. Proteolytic processing starts at the site between the spacer peptide 1 (SP1) and the nucleocapsid (NC) and culminates in the separation of SP1 from the capsid protein (CA). The initial cleavage event effectively separates the NC-gRNA layer from the viral membrane inducing gRNA condensation. The last event activates a molecular switch that triggers a late maturation event, namely the assembly of the mature HIV-1 capsid around the ribonucleic protein. During maturation, the matrix protein (MA), that is embedded to the viral membrane via a myristoyl group, is cleaved from CA, resulting in reordering of the MA lattice and alteration of the composition of the lipid membrane. Although several structures of immature and mature CA and MA hexamers have been solved by sub tomogram averaging, the molecular mechanism connecting the multiple events that occur during HIV-1 maturation are still unclear. Here, we propose to utilize full-scale molecular dynamics simulations, integrating shaped-based coarse- grained and atomistic methods, to determine motion-structures that reveal the mechanistic details of HIV-1 virion maturation. Results from the simulations will inform the engineering of protein mutants for structural analysis and guide the experimental design of functional analyses and testing of hypotheses derived from the molecular simulations.

项目摘要 在新萌芽的HIV-1颗粒变成融合性(和感染性)之前，它必须经历 成熟。在成熟过程中，病毒粒子的内容物从球形外壳转变为 病毒蛋白酶对55 kDa Gag多聚蛋白进行一系列切割后的锥形结构。 蛋白质降解过程始于间隔肽1(SP1)和 核衣壳(NC)，并最终从衣壳蛋白(CA)中分离出SP1。这个 最初的切割事件有效地将NC-gRNA层从病毒膜上分离出来 诱导gRNA缩合。最后一个事件激活了一个分子开关，从而触发了一种延迟 成熟事件，即成熟的HIV-1衣壳在核糖核周围组装 蛋白。在成熟过程中，嵌入到病毒膜上的基质蛋白(MA)通过 肉豆蔻基从CA上裂解，导致MA晶格的重新排序和改变 脂膜的组成。尽管不成熟和成熟的CA的几种结构 而MA六角体已经通过亚断层图像平均来解决，分子机制 HIV-1成熟过程中发生的多个事件之间的联系仍不清楚。在这里，我们 建议利用全尺度分子动力学模拟，将基于形状的粗分子动力学模拟 粒化和原子化的方法，以确定揭示机械的运动结构 HIV-1病毒粒子成熟的细节。模拟的结果将向工程人员提供 蛋白质突变体用于结构分析和指导功能分析的实验设计 以及对来自分子模拟的假设进行检验。