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 在一个新出芽的HIV-1颗粒变得融合（和感染）之前，它必须经历 成熟在成熟过程中，病毒体的内容物从球形壳转变为球形壳。 在病毒蛋白酶对55 kDa Gag多蛋白进行一系列切割后，形成锥形结构。 蛋白水解过程开始于间隔肽1（SP1）和蛋白水解酶之间的位点。 核衣壳（NC）的分离，并在SP1与衣壳蛋白（CA）的分离中达到高潮。的 初始切割事件有效地将NC-gRNA层与病毒膜分离 诱导gRNA缩合。最后一个事件激活了一个分子开关 成熟事件，即成熟的HIV-1衣壳在核糖核酸周围的组装， 蛋白在成熟过程中，基质蛋白（MA）通过免疫球蛋白（IgM）包埋在病毒膜上， 肉豆蔻酰基从CA上裂解，导致MA晶格的重排和 脂质膜的组成。虽然未成熟和成熟CA的几个结构 和MA六聚体已经解决了亚断层图像平均，分子机制 HIV-1成熟过程中发生的多个事件之间的联系仍然不清楚。这里我们 建议利用全尺度分子动力学模拟，整合基于形状的粗- 颗粒和原子的方法，以确定运动结构，揭示了机械 HIV-1病毒粒子成熟的细节。模拟结果将告知工程师， 蛋白质突变体的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的检验。