The efficacy of vaccines against the SARS-CoV-2 virus significantly declines with the emergence of mutant strains, prompting investigation into the feasibility of targeting highly conserved but often cryptic regions on the S2 domain of spike protein. Using tools from molecular dynamics, we find that exposure of a conserved S2 epitope located in the central helices below the receptor binding domains would require large-scale motion beyond receptor binding domain up-down motion, but, along the reaction coordinates we explored, it is unlikely to be exposed by such large-scale dynamic fluctuations of the S1 domain without any external facilitating factors, despite some previous computational evidence suggesting transient exposure of this region. Furthermore, glycans, particularly those on N165 and N234, hinder S2-exposing opening dynamics, and thus stabilize spike in addition to immunologically shielding the protein surface. Although the S2 epitope region examined here is central to large-scale conformational changes during viral entry, free energy landscape analysis obtained using the path coordinate formalism reveals no inherent “loaded spring” effect, suggesting that a vaccine immunogen would tend to present the epitope in a prefusion-like conformation and may be effective in neutralization. These findings contribute to a deeper understanding of the dynamic origins of the function of the spike protein, as well as further characterizing the feasibility of the S2 epitope as a therapeutic target.

中文翻译：

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测试针对 SARS-CoV-2 刺突蛋白 S2 结构域上的保守区域的可行性

随着突变株的出现，针对 SARS-CoV-2 病毒的疫苗功效显着下降，这促使人们研究针对刺突蛋白 S2 结构域上高度保守但往往隐蔽的区域的可行性。使用分子动力学工具，我们发现位于受体结合域下方中央螺旋的保守 S2 表位的暴露需要超出受体结合域上下运动的大规模运动，但是，沿着我们探索的反应坐标，它尽管之前的一些计算证据表明该区域短暂暴露，但在没有任何外部促进因素的情况下，不太可能受到 S1 域如此大规模的动态波动的影响。此外，聚糖，特别是 N165 和 N234 上的聚糖，会阻碍 S2 暴露的开放动力学，从而除了免疫保护蛋白质表面之外还可以稳定尖峰。尽管这里检查的 S2 表位区域是病毒进入期间大规模构象变化的核心，但使用路径坐标形式获得的自由能景观分析显示没有固有的“加载弹簧”效应，这表明疫苗免疫原倾向于在类似预融合的构象，可能有效中和。这些发现有助于更深入地了解刺突蛋白功能的动态起源，并进一步表征 S2 表位作为治疗靶点的可行性。