Evolutionary Bioinformatics Laboratory, Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Viruses. 2024 Aug 25;16(9):1358. doi: 10.3390/v16091358.
The COVID-19 pandemic saw the emergence of various Variants of Concern (VOCs) that took the world by storm, often replacing the ones that preceded them. The characteristic mutant constellations of these VOCs increased viral transmissibility and infectivity. Their origin and evolution remain puzzling. With the help of data mining efforts and the GISAID database, a chronology of 22 haplotypes described viral evolution up until 23 July 2023. Since the three-dimensional atomic structures of proteins corresponding to the identified haplotypes are not available, ab initio methods were here utilized. Regions of intrinsic disorder proved to be important for viral evolution, as evidenced by the targeted change to the nucleocapsid (N) protein at the sequence, structure, and biochemical levels. The linker region of the N-protein, which binds to the RNA genome and self-oligomerizes for efficient genome packaging, was greatly impacted by mutations throughout the pandemic, followed by changes in structure and intrinsic disorder. Remarkably, VOC constellations acted co-operatively to balance the more extreme effects of individual haplotypes. Our strategy of mapping the dynamic evolutionary landscape of genetically linked mutations to the N-protein structure demonstrates the utility of ab initio modeling and deep learning tools for therapeutic intervention.
COVID-19 大流行期间出现了各种令人关注的变异株 (VOCs)，这些变异株席卷全球，经常取代之前的变异株。这些 VOC 的特征突变体组合增加了病毒的传染性和感染力。它们的起源和进化仍然令人费解。在数据挖掘工作和 GISAID 数据库的帮助下，直到 2023 年 7 月 23 日，对 22 个单倍型进行了描述病毒进化的时间线。由于与鉴定的单倍型相对应的蛋白质的三维原子结构不可用，因此这里使用了从头开始的方法。事实证明，无序区域对于病毒进化很重要，这可以从核衣壳 (N) 蛋白在序列、结构和生化水平上的靶向变化得到证明。N 蛋白的连接区与 RNA 基因组结合并自我寡聚化以实现有效的基因组包装，在整个大流行过程中受到突变的极大影响，随后结构和无序区域发生变化。值得注意的是，VOC 组合协同作用以平衡个别单倍型更极端的影响。我们将遗传关联突变映射到 N 蛋白结构的动态进化景观的策略表明，从头开始建模和深度学习工具可用于治疗干预。
