Department of Physics, University of Alberta, Edmonton, Canada.
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Canada.
PLoS Comput Biol. 2023 May 19;19(5):e1011124. doi: 10.1371/journal.pcbi.1011124. eCollection 2023 May.
Coronaviruses (CoVs) use -1 programmed ribosomal frameshifting stimulated by RNA pseudoknots in the viral genome to control expression of enzymes essential for replication, making CoV pseudoknots a promising target for anti-coronaviral drugs. Bats represent one of the largest reservoirs of CoVs and are the ultimate source of most CoVs infecting humans, including those causing SARS, MERS, and COVID-19. However, the structures of bat-CoV frameshift-stimulatory pseudoknots remain largely unexplored. Here we use a combination of blind structure prediction followed by all-atom molecular dynamics simulations to model the structures of eight pseudoknots that, together with the SARS-CoV-2 pseudoknot, are representative of the range of pseudoknot sequences in bat CoVs. We find that they all share some key qualitative features with the pseudoknot from SARS-CoV-2, notably the presence of conformers with two distinct fold topologies differing in whether or not the 5' end of the RNA is threaded through a junction, and similar conformations for stem 1. However, they differed in the number of helices present, with half sharing the 3-helix architecture of the SARS-CoV-2 pseudoknot but two containing 4 helices and two others only 2. These structure models should be helpful for future work studying bat-CoV pseudoknots as potential therapeutic targets.
冠状病毒（CoV）利用病毒基因组中 RNA 假结刺激的 -1 程序性核糖体移码来控制复制所需酶的表达，这使得 CoV 假结成为抗冠状病毒药物的有前途的靶标。蝙蝠代表了最大的 CoV 库之一，是感染人类的大多数 CoV 的最终来源，包括导致 SARS、MERS 和 COVID-19 的 CoV。然而，蝙蝠-CoV 移码刺激假结的结构在很大程度上仍未得到探索。在这里，我们使用盲法结构预测与全原子分子动力学模拟相结合的方法，对 8 个假结结构进行建模，这些假结与 SARS-CoV-2 假结一起，代表了蝙蝠 CoV 中假结序列的范围。我们发现它们都与 SARS-CoV-2 假结具有一些关键的定性特征，特别是存在两种具有不同折叠拓扑结构的构象，其区别在于 RNA 的 5'端是否穿过连接点，以及茎 1 的相似构象。然而，它们在存在的螺旋数量上有所不同，其中一半具有 SARS-CoV-2 假结的 3 螺旋结构，但有两个含有 4 个螺旋，另外两个只有 2 个。这些结构模型应该有助于未来研究蝙蝠-CoV 假结作为潜在的治疗靶点。
