PDF(Pubmed)
Abstract：
The SARS-CoV-2 Omicron variant containing 15 mutations, including the unique Q493R, in the spike protein receptor binding domain (S1-RBD) is highly infectious. While comparison with previously reported mutations provide some insights, the mechanism underlying the increased infections and the impact of the reversal of the unique Q493R mutation seen in BA.4, BA.5, BA.2.75, BQ.1 and XBB lineages is not yet completely understood. Here, using structural modelling and molecular dynamics (MD) simulations, we show that the Omicron mutations increases the affinity of S1-RBD for ACE2, and a reversal of the unique Q493R mutation further increases the ACE2-S1-RBD affinity. Specifically, we performed all atom, explicit solvent MD simulations using a modelled structure of the Omicron S1-RBD-ACE2 and compared the trajectories with the WT complex revealing a substantial reduction in the Cα-atom fluctuation in the Omicron S1-RBD and increased hydrogen bond and other interactions. Residue level analysis revealed an alteration in the interaction between several residues including a switch in the interaction of ACE2 D38 from S1-RBD Y449 in the WT complex to the mutated R residue (Q493R) in Omicron complex. Importantly, simulations with Revertant (Omicron without the Q493R mutation) complex revealed further enhancement of the interaction between S1-RBD and ACE2. Thus, results presented here not only provide insights into the increased infectious potential of the Omicron variant but also a mechanistic basis for the reversal of the Q493R mutation seen in some Omicron lineages and will aid in understanding the impact of mutations in SARS-CoV-2 evolution.
摘要：
SARS-CoV-2Omicron变体含有15个突变，包括独特的Q493R，在刺突蛋白受体结合域（S1-RBD）中具有高度传染性。虽然与以前报道的突变进行比较提供了一些见解，在BA.4,BA.5,BA.2.75,BQ.1和XBB谱系中观察到的感染增加的潜在机制和独特Q493R突变逆转的影响尚未完全了解.这里,使用结构建模和分子动力学(MD)模拟，我们显示Omicron突变增加了S1-RBD对ACE2的亲和力,而独特的Q493R突变的逆转进一步增加了ACE2-S1-RBD的亲和力.具体来说,我们执行了所有的原子，使用OmicronS1-RBD-ACE2的模型结构进行显式溶剂MD模拟，并将轨迹与WT复合物进行比较，发现OmicronS1-RBD中的Cα原子波动大幅减少，氢键和其他相互作用增加。残基水平分析揭示了几个残基之间相互作用的改变，包括WT复合物中的S1-RBDY449的ACE2D38与Omicron复合物中突变的R残基（Q493R）相互作用的转换。重要的是,用Revertant(无Q493R突变的Omicron)复合物模拟显示S1-RBD和ACE2之间的相互作用进一步增强。因此，本文的结果不仅为Omicron变异体的感染潜力增加提供了见解，而且为逆转某些Omicron谱系中的Q493R突变提供了机制基础，并将有助于理解突变对SARS-CoV-2进化的影响。
