Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Bioenergy and Biome Sciences Group, Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Biomolecules. 2021 Jan 19;11(1):124. doi: 10.3390/biom11010124.
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 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 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 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.
季节性流感是一种急性呼吸道疾病，会给人类人口、医疗系统和经济造成巨大损失。该疾病由包膜病毒引起，该病毒包含 8 个核糖核蛋白（RNP）复合物。每个 RNP 包含多个核蛋白（NP）拷贝、病毒基因组（vRNA）的一个片段和病毒 RNA 依赖性 RNA 聚合酶（POL），负责包装病毒基因组并执行关键功能，包括复制和转录。一个完整的 RNP 原子细节模型可以阐明病毒基因组功能的结构基础，并确定病毒治疗的潜在靶点。在这项工作中，我们使用多种结构和序列信息源以及一系列同源建模技术，包括基序匹配片段组装方法，构建了一个完整的 RNP 复合物的原子细节模型。我们的最终模型为许多突变分析实验中观察到的病毒聚合酶活性的变化提供了合理的解释。此外，我们的模型揭示了 RNP 三个主要结构成分之间的特定相互作用，包括阻止 POL 与 NP-vRNA 复合物结合的潜在靶点。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。
