Université de Paris, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France.
Equipe 3IMo, UMR1282 Infectiologie et Santé Publique, INRAE, 37380 Nouzilly, France.
Int J Mol Sci. 2022 Feb 4;23(3):1805. doi: 10.3390/ijms23031805.
Influenza A viruses are highly contagious RNA viruses that cause respiratory tract infections in humans and animals. Their non-structural protein NS1, a homodimer of two 230-residue chains, is the main viral factor in counteracting the antiviral defenses of the host cell. Its RNA-binding domain is an obligate dimer that is connected to each of the two effector domains by a highly flexible unstructured linker region of ten amino acids. The flexibility of NS1 is a key property that allows its effector domains and its RNA binding domain to interact with several protein partners or RNAs. The three-dimensional structures of full-length NS1 dimers revealed that the effector domains could adopt three distinct conformations as regards their mutual interactions and their orientation relative to the RNA binding domain (closed, semi-open and open). The origin of this structural polymorphism is currently being investigated and several hypotheses are proposed, among which one posits that it is a strain-specific property. In the present study, we explored through computational molecular modeling the dynamic and flexibility properties of NS1 from three important influenza virus A strains belonging to three distinct subtypes (H1N1, H6N6, H5N1), for which at least one conformation is available in the Protein Data Bank. In order to verify whether NS1 is stable in three forms for the three strains, we constructed homology models if the corresponding forms were not available in the Protein Data Bank. Molecular dynamics simulations were performed in order to predict the stability over time of the three distinct sequence variants of NS1, in each of their three distinct conformations. Our results favor the co-existence of three stable structural forms, regardless of the strain, but also suggest that the length of the linker, along with the presence of specific amino acids, modulate the dynamic properties and the flexibility of NS1.
甲型流感病毒是高度传染性的 RNA 病毒，可引起人类和动物的呼吸道感染。其非结构蛋白 NS1 是一种由两条 230 个残基组成的同源二聚体，是宿主细胞抗病毒防御的主要病毒因子。其 RNA 结合结构域是一个必需的二聚体，通过一个由十个氨基酸组成的高度灵活的无规卷曲连接区与两个效应结构域中的每一个连接。NS1 的灵活性是其效应结构域和 RNA 结合结构域能够与几种蛋白伴侣或 RNA 相互作用的关键特性。全长 NS1 二聚体的三维结构表明，效应结构域在其相互作用及其相对于 RNA 结合结构域的取向方面可以采用三种不同的构象（关闭、半开和打开）。这种结构多态性的起源目前正在研究中，提出了几种假设，其中一种假设认为它是一种株特异性特性。在本研究中，我们通过计算分子建模探索了属于三种不同亚型（H1N1、H6N6、H5N1）的三种重要甲型流感病毒株的 NS1 的动态和灵活性特性，对于至少一种构象，在蛋白质数据库中都有其相应的构象。为了验证 NS1 在三种形式下是否对三种株都是稳定的，我们构建了同源模型，如果蛋白质数据库中没有相应的形式。进行了分子动力学模拟，以预测 NS1 的三种不同序列变体在其三种不同构象中的随时间的稳定性。我们的结果倾向于三种稳定结构形式的共存，而不管株的情况如何，但也表明连接区的长度以及特定氨基酸的存在，调节 NS1 的动态特性和灵活性。
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