Inositol Hexakisphosphate (IP6) Accelerates Immature HIV-1 Gag Protein Assembly toward Kinetically Trapped Morphologies.
Inositol Hexakisphosphate (IP6) Accelerates Immature HIV-1 Gag Protein Assembly toward Kinetically Trapped Morphologies.
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DOI：
10.1021/jacs.2c02568
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发表时间：
2022-06-15
影响因子：
15
通讯作者：
Voth, Gregory A.
中科院分区：
文献类型：
--
作者：
Pak, Alexander J.;Gupta, Manish;Yeager, Mark;Voth, Gregory A.
在HIV - 1生命周期的后期阶段，未成熟的病毒粒子是由Gag多聚蛋白的协同活动产生的，这主要由衣壳（CA）和间隔肽1（SP1）结构域介导，它们组装成球形晶格，包装病毒基因组RNA，并使质膜变形。最近，肌醇六磷酸（IP6）已被确定为一种必需的组装辅因子，它能在体内有效地产生未成熟病毒粒子，在体外有效地产生未成熟病毒样颗粒。然而，到目前为止，基于独立的功能、结构和动力学研究，已经提出了IP6的几种不同的机制作用。在这项工作中，我们利用粗粒度（CG）分子动力学（MD）模拟和自由能计算，研究了IP6对CA/SP1组装的结构结果和动力学的分子影响。在这里，我们推导了一个自下而上的、低分辨率的、隐式溶剂的CA/SP1和IP6的粗粒度模型，并在模拟体外和体内系统的条件下模拟它们的组装。我们的分析确定IP6是一种组装促进剂，它促进整个晶格的曲率产生和类似裂缝的缺陷。我们的研究结果表明，IP6诱导了动力学受限的未成熟形态，这对于病毒形态发生的后期阶段可能具有生理重要性，并且可能对病毒样颗粒技术有用。
During the late stages of the HIV-1 lifecycle, immature virions are produced by the concerted activity of Gag polyproteins, primarily mediated by the capsid (CA) and spacer peptide 1 (SP1) domains, which assemble into a spherical lattice, package viral genomic RNA, and deform the plasma membrane. Recently, inositol hexakisphosphate (IP6) has been identified as an essential assembly cofactor that efficiently produces both immature virions in vivo and immature virus-like particles in vitro. To date, however, several distinct mechanistic roles for IP6 have been proposed on the basis of independent functional, structural, and kinetic studies. In this work, we investigate the molecular influence of IP6 on the structural outcomes and dynamics of CA/SP1 assembly using coarse-grained (CG) molecular dynamics (MD) simulations and free energy calculations. Here, we derive a bottom-up, low-resolution, and implicit-solvent CG model of CA/SP1 and IP6, and simulate their assembly under conditions that emulate both in vitro and in vivo systems. Our analysis identifies IP6 as an assembly accelerant that promotes curvature generation and fissure-like defects throughout the lattice. Our findings suggest that IP6 induces kinetically trapped immature morphologies, which may be physiologically important for later stages of viral morphogenesis and potentially useful for virus-like particle technologies.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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发表时间：
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影响因子：
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