Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana; Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana.
Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana.
Infect Genet Evol. 2021 Jul;91:104815. doi: 10.1016/j.meegid.2021.104815. Epub 2021 Mar 24.
The D614G variant of SARS-CoV-2 S-protein emerged in early 2020 and quickly became the dominant circulating strain in Europe and its environs. The variant was characterized by the higher viral load, which is not associated with disease severity, higher incorporation into the virion, and high cell entry via ACE-2 and TMPRSS2. Previous strains of the coronavirus and the current SARS-CoV-2 have demonstrated the selection of mutations as a mechanism of escaping immune responses. In this study, we used molecular dynamics simulation and MM-PBSA binding energy analysis to provide insights into the behaviour of the D614G S-protein at the molecular level and describe the neutralization mechanism of this variant. Our results show that the D614G S-protein adopts distinct conformational dynamics which is skewed towards the open-state conformation more than the closed-state conformation of the wild-type S-protein. Residue-specific variation of amino acid flexibility and domain-specific RMSD suggest that the mutation causes an allosteric conformational change in the RBD. Evaluation of the interaction energies between the S-protein and neutralizing antibodies show that the mutation may enhance, reduce or not affect the neutralizing interactions depending on the neutralizing antibody, especially if it targets the RBD. The results of this study have shed insights into the behaviour of the D614G S-protein at the molecular level and provided a glimpse of the neutralization mechanism of this variant.
SARS-CoV-2 刺突蛋白 D614G 变体于 2020 年初出现，并迅速成为欧洲及其周边地区的主要流行株。该变体的特点是病毒载量较高，与疾病严重程度无关，更高比例地整合到病毒粒子中，以及通过 ACE-2 和 TMPRSS2 实现高细胞进入。以前的冠状病毒株和当前的 SARS-CoV-2 已经证明了突变的选择是逃避免疫反应的一种机制。在这项研究中，我们使用分子动力学模拟和 MM-PBSA 结合能分析，从分子水平上深入了解 D614G S 蛋白的行为，并描述该变体的中和机制。我们的结果表明，D614G S 蛋白采用了独特的构象动力学，其开放构象的倾向性大于野生型 S 蛋白的闭合构象。残基特异性氨基酸灵活性变化和结构域特异性 RMSD 表明，该突变导致 RBD 发生变构构象变化。评估 S 蛋白与中和抗体之间的相互作用能表明，该突变可能增强、减弱或不影响中和相互作用，具体取决于中和抗体，尤其是针对 RBD 的中和抗体。这项研究的结果深入了解了 D614G S 蛋白在分子水平上的行为，并为该变体的中和机制提供了一些见解。
