Seasonal flu is an acute respiratory disease that exacts a massive toll on human populations, healthcare systems and economies. The disease is caused by an enveloped Influenza virus containing eight ribonucleoprotein (RNP) complexes. Each RNP incorporates multiple copies of nucleoprotein (NP), a fragment of the viral genome (vRNA), and a viral RNA-dependent RNA polymerase (POL), and is responsible for packaging the viral genome and performing critical functions including replication and transcription. A complete model of an Influenza RNP in atomic detail can elucidate the structural basis for viral genome functions, and identify potential targets for viral therapeutics. In this work we construct a model of a complete Influenza A RNP complex in atomic detail using multiple sources of structural and sequence information and a series of homology-modeling techniques, including a motif-matching fragment assembly method. Our final model provides a rationale for experimentally-observed changes to viral polymerase activity in numerous mutational assays. Further, our model reveals specific interactions between the three primary structural components of the RNP, including potential targets for blocking POL-binding to the NP-vRNA complex. The methods developed in this work open the possibility of elucidating other functionally-relevant atomic-scale interactions in additional RNP structures and other biomolecular complexes.

中文翻译：

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在原子细节中模拟甲型流感NP-vRNA-聚合酶复合物

季节性流感是一种急性呼吸道疾病，对人类，医疗保健系统和经济造成巨大损失。该疾病是由含有八种核糖核蛋白（RNP）复合物的包膜流感病毒引起的。每个RNP都包含核蛋白（NP），病毒基因组（vRNA）片段和病毒RNA依赖性RNA聚合酶（POL）的多个副本，并负责包装病毒基因组并执行关键功能，包括复制和转录。一个的完整模型流感RNP在原子细节可以阐明为病毒基因组的功能的结构的基础上，并确定病毒疗法的潜在靶标。在这项工作中，我们构建了完整的甲型流感的模型RNP在原子细节上复杂，使用多种来源的结构和序列信息以及一系列同源性建模技术，包括基序匹配片段组装方法。我们的最终模型为在众多突变试验中实验观察到的病毒聚合酶活性变化提供了理论依据。此外，我们的模型揭示了RNP的三个主要结构成分之间的特定相互作用，包括可能阻止POL与NP-vRNA复合物结合的靶标。这项工作中开发的方法为阐明其他RNP结构和其他生物分子复合物中其他功能相关的原子尺度相互作用提供了可能性。