Department of Microbiology, Jashore University of Science and Technology, Jashore, Bangladesh.
Division of Poverty, Health, and Nutrition, International Food Policy Research Institute, Bangladesh.
J Med Virol. 2022 Mar;94(3):1035-1049. doi: 10.1002/jmv.27416. Epub 2021 Nov 1.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into eight fundamental clades with four of these clades (G, GH, GR, and GV) globally prevalent in 2020. To explain plausible epistatic effects of the signature co-occurring mutations of these circulating clades on viral replication and transmission fitness, we proposed a hypothetical model using in silico approach. Molecular docking and dynamics analyses showed the higher infectiousness of a spike mutant through more favorable binding of G with the elastase-2. RdRp mutation p.P323L significantly increased genome-wide mutations (p < 0.0001), allowing for more flexible RdRp (mutated)-NSP8 interaction that may accelerate replication. Superior RNA stability and structural variation at NSP3:C241T might impact protein, RNA interactions, or both. Another silent 5'-UTR:C241T mutation might affect translational efficiency and viral packaging. These four G-clade-featured co-occurring mutations might increase viral replication. Sentinel GH-clade ORF3a:p.Q57H variants constricted the ion-channel through intertransmembrane-domain interaction of cysteine(C81)-histidine(H57). The GR-clade N:p.RG203-204KR would stabilize RNA interaction by a more flexible and hypo-phosphorylated SR-rich region. GV-clade viruses seemingly gained the evolutionary advantage of the confounding factors; nevertheless, N:p.A220V might modulate RNA binding with no phenotypic effect. Our hypothetical model needs further retrospective and prospective studies to understand detailed molecular events and their relationship to the fitness of SARS-CoV-2.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 已经进化成八个基本谱系，其中四个谱系（G、GH、GR 和 GV）在 2020 年在全球流行。为了解释这些流行谱系的特征性共现突变对病毒复制和传播适应性的可能上位效应，我们使用计算机模拟方法提出了一个假设模型。分子对接和动力学分析表明，通过更有利于 G 与弹性蛋白酶-2 的结合，刺突突变体具有更高的传染性。RdRp 突变 p.P323L 显著增加了全基因组突变（p<0.0001），允许更灵活的 RdRp（突变）-NSP8 相互作用，从而可能加速复制。NSP3:C241T 处的 RNA 稳定性和结构变化更好，可能影响蛋白质、RNA 相互作用或两者兼而有之。另一个沉默的 5'-UTR:C241T 突变可能影响翻译效率和病毒包装。这四个 G 谱系特征的共现突变可能会增加病毒复制。Sentinel GH 谱系 ORF3a:p.Q57H 变体通过半胱氨酸（C81）-组氨酸（H57）之间的跨膜结构域相互作用限制了离子通道。GR 谱系 N:p.RG203-204KR 通过更灵活和低磷酸化的富含 SR 的区域稳定 RNA 相互作用。GV 谱系病毒似乎获得了混杂因素的进化优势；然而，N:p.A220V 可能会调节 RNA 结合而没有表型效应。我们的假设模型需要进一步的回顾性和前瞻性研究，以了解详细的分子事件及其与 SARS-CoV-2 适应性的关系。
