Multiscale Computational Microscopy of HIV-1

HIV-1 的多尺度计算显微镜

• 批准号: 10756808
• 负责人: Rommie E Amaro
• 金额: $ 71.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10756808
• 关键词: 2019-nCoV; AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Antigens; Back; Biology; Cells; Chimeric Proteins; Collaborations; Crowding; Cryo-electron tomography; Cryoelectron Microscopy; Data; Data Set; Disease; Elements; Exhibits; Future Generations; Glycocalyx; Goals; HIV; HIV vaccine; HIV-1; Heparitin Sulfate; Human; Immune system; Infection; Infection prevention; Influenza; Knowledge; Link; Methods; Microscope; Microscopy; Modeling; Molecular Structure; Mucins; Mutate; Outcome; Pattern; Persons; Physiological; Play; Polysaccharides; Post-Translational Protein Processing; Protein Dynamics; RNA; Resolution; Retroviridae; Scientist; Series; Site; Structural Biologist; Structure; Surface; Techniques; Therapeutic; Time; Translating; United States National Institutes of Health; Utah; Vaccines; Viral; Viral Fusion Proteins; Viral Proteins; Virion; Virus; advanced simulation; density; design; env Gene Products; experimental study; flexibility; immunogenic; improved; in vivo; infection rate; insight; interest; model building; molecular dynamics; novel; receptor; simulation; small molecule; structural biology

ABSTRACT The human immunodeficiency virus 1 (HIV-1) is the RNA retrovirus that causes acquired immunodeficiency syndrome (AIDS), a disease that has killed over 40 million people worldwide and infected more than twice that. Continued high infection rates has made understanding of HIV biology and vaccines a high priority. A key molecule involved in both infection and vaccine efforts is the HIV-1 Envelope protein (Env). Experimental structural biology techniques have characterized the basic structure of Env, but they are unable to provide details about the extensive N-linked glycan shield nor inform on the flexibility and dynamics of Env. In this proposal, we envision using all-atom molecular dynamics simulations as a `computational microscope,' to provide insights into the dynamics of Env that are unattainable with current experimental techniques. Together with top flight experimentalists, we will develop and simulate a series of models to explore the dynamics of Env as well as its interactions with co-receptors and the cell glycocalyx, in unprecedented detail. In addition, we will use advanced simulation techniques to optimize immunogen design as well as provide critical information about hitherto unseen druggable sites in Env.

摘要 人类免疫缺陷病毒1（HIV-1）是一种RNA逆转录病毒， 免疫缺陷综合症（艾滋病），一种在全世界造成4 000多万人死亡的疾病 感染了两倍多的病毒持续的高感染率使人们了解到， 艾滋病毒生物学和疫苗是高度优先事项。一种与感染和疫苗有关的关键分子 HIV-1包膜蛋白（Env）。实验结构生物学技术 描述了Env的基本结构，但他们无法提供有关Env的详细信息。 广泛的N-连接的聚糖屏蔽，也没有提供Env的灵活性和动力学信息。在这 建议，我们设想使用全原子分子动力学模拟作为一个“计算 显微镜，“以提供对Env动力学的见解，这是目前无法实现的。 实验技术我们将与一流的实验人员一起， 一系列模型来探索Env的动力学及其与辅助受体的相互作用 和细胞的糖萼，前所未有的详细。此外，我们将使用先进的模拟 优化免疫原设计的技术，以及提供迄今为止关于 环境中看不见的可药用位点。