class='head no_bottom_margin' id='sec1title'>Int'/> Nothing to Sneeze At: A Dynamic and Integrative Computational Model of an Influenza A Virion
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Nothing to Sneeze At: A Dynamic and Integrative Computational Model of an Influenza A Virion

机译:不容小::甲型流感病毒的动态综合计算模型

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摘要

class="head no_bottom_margin" id="sec1title">IntroductionThere have been a number of structural studies on the influenza A virus (e.g. ), which is surrounded by a pleomorphic lipid bilayer envelope that imposes challenges for high-resolution structural characterization. These have provided important details about the morphology of the virions and the distribution of their surface glycoproteins, but structural studies that include detailed analysis of the lipids are lacking. Indeed, the lipid composition of the influenza A envelope has only recently been established (). The importance of lipids in the stability of the influenza A virion is clear from a number of studies. Both H5N1 and H1N1 viruses were more stable in water when grown in mammalian cells versus counterparts propagated in avian cells, even for viruses with the same genetic background (). Only the lipid composition and the glycosylation states of the viruses differed. A progressive ordering with decreasing temperature for influenza A lipids studied by nuclear magnetic resonance (NMR) spectroscopy implicated the lipids in seasonal behavior (). Lipids form much of the outer protective shell of the influenza A virion, and they are a logical target for additional biophysical analysis.Molecular dynamics simulations provide an opportunity to integrate structural data from a variety of experimental sources. For example, an impressive set of 0.1 μs, 64 million atom, molecular dynamics simulations were used to model the HIV-1 capsid (). However, these simulations omitted the lipid envelope of the virus, enabling the method for model construction to be strongly guided by the experimental electron densities from cryo-electron microscopy (cryo-EM). A multiscale approach was used for examining the full-scale immature HIV-1 virion (). The system was highly coarse-grained (CG) with a protein model corresponding to approximately 7–9 amino acid residues per particle, and used a relatively simple (DOPS/DOPC) and symmetric lipid bilayer membrane. An all-atom simulation of a complete virus, including its RNA core, has also been performed (), based on the crystal structure of satellite tobacco mosaic virus. This virus contains no lipid, and the viral envelope consists of 60 copies of a single protein arranged in an icosahedron. Recent modeling of nonenveloped icosahedral virions revealed their mechanical properties and possible mechanisms for capsid dissolution via calcium ion depletion (). Likewise, recent modeling of the rabbit hemorrhagic disease virus (), which is also icosahedral and contains no lipids, was based on fitting the model to available X-ray diffraction and cryo-EM data. Previous influenza virus membrane protein simulations have largely been focused on isolated components of the virion, e.g. modeling of fusion peptide activity () or of hemagglutinin (HA) clustering in model membranes ().In this study, we use CG molecular dynamics simulations () building on structural information from X-ray crystallography (), NMR spectroscopy (), cryo-EM (), and lipidomics data (href="#bib18" rid="bib18" class=" bibr popnode">Gerl et al., 2012) to produce a detailed (near atomic resolution) computational model of the influenza A virion. This integration of structural information from a number of sources has allowed us to perform microsecond-scale CG molecular dynamics simulations of the outer envelope of an enveloped virion in explicit solvent. These simulations reveal the structural and dynamic properties of the viral envelope which contribute to its stability, and will allow us to initiate models of virion/target cell recognition. The complex lipid dynamics revealed in our simulations extend and complement static structural data from cryo-EM and related experimental approaches. We provide the virion coordinates and simulation parameters openly to the community.
机译:<!-fig ft0-> <!-fig @ position =“ anchor” mode =文章f4-> <!-fig mode =“ anchred” f5-> <!-fig / graphic | fig / alternatives / graphic mode =“ anchored” m1-> class =“ head no_bottom_margin” id =“ sec1title”>简介对甲型流感病毒(例如)进行了许多结构研究,其中被脂质体双层包膜包围,对高分辨率的结构表征提出了挑战。这些已经提供了有关病毒体的形态及其表面糖蛋白分布的重要细节,但是缺乏包括对脂质进行详细分析的结构研究。确实,甲型流感包膜的脂质成分只是最近才被确定。从许多研究中可以清楚地看出脂质在甲型流感病毒颗粒稳定性中的重要性。当在哺乳动物细胞中生长时,H5N1和H1N1病毒在水中都更稳定,而在禽类细胞中繁殖的对应物,即使对于具有相同遗传背景的病毒也是如此。病毒的脂质组成和糖基化状态不同。通过核磁共振(NMR)光谱研究的甲型流感脂质温度降低的渐进性排序将脂质归因于季节性行为()。脂质构成了甲型流感病毒粒子的大部分保护层,它们是进行其他生物物理分析的逻辑目标。分子动力学模拟为整合来自各种实验来源的结构数据提供了机会。例如,一组令人印象深刻的0.1μs,6400万个原子的分子动力学模拟被用来模拟HIV-1衣壳()。但是,这些模拟省略了病毒的脂质包膜,从而使模型构建的方法能够受到低温电子显微镜(cryo-EM)的实验电子密度的严格指导。多尺度方法用于检查完整的未成熟HIV-1病毒体()。该系统是高度粗粒化(CG)的,其蛋白质模型对应每个颗粒大约7–9个氨基酸残基,并使用相对简单的(DOPS / DOPC)和对称的脂质双层膜。基于卫星烟草花叶病毒的晶体结构,还对一个完整的病毒,包括其RNA核心,进行了全原子模拟。该病毒不含脂质,病毒包膜由排列在二十面体中的单个蛋白质的60个拷贝组成。最近对未包封的二十面体病毒粒子的建模揭示了它们的机械性能以及通过钙离子耗竭而使衣壳溶解的可能机理()。同样,兔出血性疾病病毒()也是二十面体且不含脂质,最近的建模是基于该模型对可用X射线衍射和冷冻EM数据的拟合。以前的流感病毒膜蛋白模拟主要集中在病毒体的分离成分上,例如模型膜中融合肽活性()或血凝素(HA)簇的模型化()。在这项研究中,我们使用CG分子动力学模拟()建立在X射线晶体学(),NMR光谱学(),冷冻机的结构信息的基础上-EM()和脂质组学数据(href="#bib18" rid="bib18" class=" bibr popnode"> Gerl等人,2012 )来生成详细的(接近原子分辨率)计算结果甲型病毒粒子的模型。来自许多来源的结构信息的集成使我们能够在显式溶剂中对包膜病毒体的外部包膜进行微秒级CG分子动力学模拟。这些模拟揭示了病毒包膜的结构和动态特性,有助于其稳定性,并使我们能够启动病毒体/靶细胞识别的模型。我们的模拟中揭示的复杂脂质动力学扩展并补充了来自cryo-EM和相关实验方法的静态结构数据。我们向社区公开提供病毒体坐标和模拟参数。

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