Shapify:SARS-CoV-2 框架移位假结的途径。
Shapify: Paths to SARS-CoV-2 frameshifting pseudoknot.
机构信息
Department of Computer Science, University of Victoria, Victoria, British Columbia, Canada.
Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada.
出版信息
PLoS Comput Biol. 2023 Feb 28;19(2):e1010922. doi: 10.1371/journal.pcbi.1010922. eCollection 2023 Feb.
Multiple coronaviruses including MERS-CoV causing Middle East Respiratory Syndrome, SARS-CoV causing SARS, and SARS-CoV-2 causing COVID-19, use a mechanism known as -1 programmed ribosomal frameshifting (-1 PRF) to replicate. SARS-CoV-2 possesses a unique RNA pseudoknotted structure that stimulates -1 PRF. Targeting -1 PRF in SARS-CoV-2 to impair viral replication can improve patients' prognoses. Crucial to developing these therapies is understanding the structure of the SARS-CoV-2 -1 PRF pseudoknot. Our goal is to expand knowledge of -1 PRF structural conformations. Following a structural alignment approach, we identify similarities in -1 PRF pseudoknots of SARS-CoV-2, SARS-CoV, and MERS-CoV. We provide in-depth analysis of the SARS-CoV-2 and MERS-CoV -1 PRF pseudoknots, including reference and noteworthy mutated sequences. To better understand the impact of mutations, we provide insight on -1 PRF pseudoknot sequence mutations and their effect on resulting structures. We introduce Shapify, a novel algorithm that given an RNA sequence incorporates structural reactivity (SHAPE) data and partial structure information to output an RNA secondary structure prediction within a biologically sound hierarchical folding approach. Shapify enhances our understanding of SARS-CoV-2 -1 PRF pseudoknot conformations by providing energetically favourable predictions that are relevant to structure-function and may correlate with -1 PRF efficiency. Applied to the SARS-CoV-2 -1 PRF pseudoknot, Shapify unveils previously unknown paths from initial stems to pseudoknotted structures. By contextualizing our work with available experimental data, our structure predictions motivate future RNA structure-function research and can aid 3-D modeling of pseudoknots.
多种冠状病毒,包括导致中东呼吸综合征的 MERS-CoV、导致 SARS 的 SARS-CoV 和导致 COVID-19 的 SARS-CoV-2,都使用一种称为 -1 核糖体移码(-1 PRF)的机制进行复制。SARS-CoV-2 具有独特的 RNA 假结结构,可刺激 -1 PRF。靶向 SARS-CoV-2 的 -1 PRF 以损害病毒复制可以改善患者的预后。开发这些疗法的关键是了解 SARS-CoV-2 -1 PRF 假结的结构。我们的目标是扩展 -1 PRF 结构构象的知识。通过结构比对方法,我们确定了 SARS-CoV-2、SARS-CoV 和 MERS-CoV 的 -1 PRF 假结之间的相似性。我们对 SARS-CoV-2 和 MERS-CoV -1 PRF 假结进行了深入分析,包括参考序列和值得注意的突变序列。为了更好地理解突变的影响,我们提供了关于 -1 PRF 假结序列突变及其对产生结构的影响的见解。我们引入了 Shapify,这是一种新算法,它可以根据 RNA 序列,将结构反应性(SHAPE)数据和部分结构信息整合到一个生物合理的分层折叠方法中,输出 RNA 二级结构预测。Shapify 通过提供与结构功能相关且可能与 -1 PRF 效率相关的能量有利预测,增强了我们对 SARS-CoV-2 -1 PRF 假结构象的理解。应用于 SARS-CoV-2 -1 PRF 假结,Shapify 揭示了从初始茎到假结结构的先前未知路径。通过将我们的工作与可用的实验数据联系起来,我们的结构预测为未来的 RNA 结构-功能研究提供了动力,并有助于假结的 3-D 建模。