Emerging SARS-CoV-2 variants raise concerns about our ability to withstand the Covid-19 pandemic, and therefore, understanding mechanistic differences of those variants is crucial. In this study, we investigate disparities between the SARS-CoV-2 wild type and five variants that emerged in late 2020, focusing on the structure and dynamics of the spike protein interface with the human angiotensin-converting enzyme 2 (ACE2) receptor, by using crystallographic structures and extended analysis of microsecond molecular dynamics simulations. Dihedral angle principal component analysis (PCA) showed the strong similarities in the spike receptor binding domain (RBD) dynamics of the Alpha, Beta, Gamma, and Delta variants, in contrast with those of WT and Epsilon. Dynamical perturbation networks and contact PCA identified the peculiar interface dynamics of the Delta variant, which cannot be directly imputable to its specific L452R and T478K mutations since those residues are not in direct contact with the human ACE2 receptor. Our outcome shows that in the Delta variant the L452R and T478K mutations act synergistically on neighboring residues to provoke drastic changes in the spike/ACE2 interface; thus a singular mechanism of action eventually explains why it dominated over preceding variants.

中文翻译：

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通过接触扰动分析解释 SARS-CoV-2 Delta 变体的奇异界面动力学

新出现的 SARS-CoV-2 变体引起了人们对我们抵御 Covid-19 大流行的能力的担忧，因此，了解这些变体的机制差异至关重要。在这项研究中，我们调查了 SARS-CoV-2 野生型和 2020 年底出现的五种变种之间的差异，重点关注刺突蛋白与人类血管紧张素转换酶 2 (ACE2) 受体界面的结构和动态，通过使用晶体结构和微秒分子动力学模拟的扩展分析。二面角主成分分析 (PCA) 显示 Alpha、Beta、Gamma 和 Delta 变体的刺突受体结合域 (RBD) 动力学与 WT 和 Epsilon 相比具有很强的相似性。动态扰动网络和接触 PCA 确定了 Delta 变体的特殊界面动力学，这不能直接归因于其特定的 L452R 和 T478K 突变，因为这些残基不与人类 ACE2 受体直接接触。我们的结果表明，在 Delta 变体中，L452R 和 T478K 突变对邻近残基协同作用，引发刺突/ACE2 界面的剧烈变化；因此，单一的作用机制最终解释了为什么它优于之前的变体。