Multiscale Computational Microscopy of HIV-1

摘要 人类免疫缺陷病毒1型(HIV-1)是导致获得性感染的RNA逆转录病毒 免疫缺陷综合症(AIDS)，一种已导致全球4000多万人死亡的疾病 并感染了两倍以上的病毒。持续的高感染率使人们理解 艾滋病毒生物学和疫苗是高度优先的。感染和疫苗都涉及的关键分子 努力的是HIV-1包膜蛋白(Env)。实验性的结构生物学技术已经 描述了环境的基本结构，但他们无法提供有关 广泛的N-连接的糖链既不能屏蔽也不能告知环境蛋白的灵活性和动态性。在这 提议，我们设想使用全原子分子动力学模拟作为一种计算 显微镜，提供对环境动态的洞察，这是目前无法实现的 实验技术。我们将与顶尖的实验者一起开发和模拟 探索Env的动力学及其与辅受体相互作用的一系列模型 和细胞糖基化，以前所未有的细节。此外，我们还将使用高级模拟 优化免疫原设计以及提供迄今为止有关免疫原的关键信息的技术 环境中未见的可用药站点。

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.