Multiscale Computational Microscopy of HIV-1

HIV-1 的多尺度计算显微镜

基本信息

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
项目类别：
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

项目摘要

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.

抽象的人免疫缺陷病毒1（HIV-1）是导致获得的RNA逆转录病毒免疫缺陷综合征（AIDS），这种疾病在全球范围内丧生超过4000万人并感染了两倍以上。持续的高感染率使艾滋病毒生物学和疫苗是高度优先级。参与感染和疫苗的关键分子努力是HIV-1包膜蛋白（ENV）。实验结构生物学技术具有表征了Env的基本结构，但他们无法提供有关广泛的N链接聚糖盾牌，也没有告知Env的灵活性和动态。在这个提案，我们设想使用全原子分子动力学模拟作为`计算显微镜，“提供有关当前无法实现的Env动态的见解实验技术。与顶级飞行实验者一起，我们将开发和模拟一系列探索ENV及其与共受体的相互作用的模型和细胞糖蛋白，史无前例的细节。此外，我们将使用高级模拟优化免疫原设计以及提供有关迄今为止的关键信息的技术在Env。