Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2's own RNA evades nsp1's host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results showed that the stem loop structure of the SARS-CoV-2 RNA 5'-untranslated region (SL1) is recognized by both nsp1's globular region and intrinsically disordered region. The recognition presumably enables selective translation of viral RNAs. Cluster analysis of the binding mode and detailed analysis of the binding poses revealed several residues involved in the SL1 recognition mechanism. The simulation results imply that the nsp1 C-terminal helices are lifted from the 40S ribosome upon the binding of SL1 to nsp1, unblocking translation of the viral RNA.

中文翻译：

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通过扩展集成仿真对SARS-CoV-2 nsp1--5'-UTR复合体进行建模

严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）的非结构蛋白1（nsp1）是一种180残基的蛋白，可阻断SARS-CoV-2感染细胞中宿主mRNA的翻译。尽管已知SARS-CoV-2自身的RNA逃避了nsp1的宿主翻译关闭，但对逃避的分子机制知之甚少。我们进行了扩展的集成分子动力学模拟，以研究病毒RNA逃逸的机制。仿真结果表明，SARS-CoV-2 RNA 5'-非翻译区（SL1）的茎环结构可被nsp1的球状区和内在无序区识别。该识别大概使病毒RNA的选择性翻译成为可能。结合模式的聚类分析和结合姿势的详细分析揭示了SL1识别机制中涉及的几个残基。仿真结果表明，nsp1 C末端螺旋从40个SL1与nsp1结合后的S核糖体，可阻断病毒RNA的翻译。