Department of Chemistry and Biology, Universität Siegen, Adolf-Reichwein-Str. 2, 57076, Siegen, Germany.
J Mol Model. 2022 Jul 19;28(8):224. doi: 10.1007/s00894-022-05206-8.
Viral-cell entry and cell-cell viral spreading processes of SARS-CoV-2 are subjected to fast evolutionary optimization because of its worldwide spreading, requiring the need for new drug developments. However, this task is still challenging, because a detailed understanding of the underlying molecular processes, mediated by the key cellular proteases TMPRSS2 and furin, is still lacking. Here, we show by large-scale atomistic calculations that binding of the ACE2 cell receptor at one of the heteromers of the SARS-CoV-2 spike leads to a release of its furin cleavage site (S1/S2), enabling an enhanced furin binding, and that this latter process promotes the binding of TMPRSS2 through the release of the TMPRSS2 cleavage site (S2') out of the ACE2-binding heteromer. Moreover, we find that, after proteolytic cleavage, improved furin binding causes that parts of the S2 subunit dissociate from the complex, suggesting that furin promotes the fusion of the S2 subunit with the cell membrane before transfer of the viral RNA. Here we show by computational means that binding of the ACE2-cell receptor at one of the heteromers of the SARS-CoV-2 spike leads to an enhanced binding of the protease furin, promoting the binding of the protease TMPRSS2. Moreover, we show that, after proteolytic cleavage, improved furin binding causes that parts of the heteromer dissociate from the spike.
新冠病毒（SARS-CoV-2）的病毒-细胞进入和细胞间病毒传播过程因其在全球范围内的传播而受到快速进化优化，这就需要开发新的药物。然而，这项任务仍然具有挑战性，因为人们对介导关键细胞蛋白酶 TMPRSS2 和弗林的基本分子过程的了解仍然不足。在这里，我们通过大规模原子计算表明，ACE2 细胞受体与 SARS-CoV-2 刺突的一个异源三聚体结合会导致其弗林切割位点（S1/S2）的释放，从而增强弗林的结合，而这一过程通过 ACE2 结合异源三聚体中 S2'切割位点的释放来促进 TMPRSS2 的结合。此外，我们发现，在蛋白水解切割后，弗林结合的增强会导致 S2 亚基的部分从复合物中解离，这表明弗林在病毒 RNA 转移之前促进 S2 亚基与细胞膜的融合。在这里，我们通过计算手段表明，ACE2 细胞受体与 SARS-CoV-2 刺突的一个异源三聚体结合会导致蛋白酶弗林的结合增强，从而促进蛋白酶 TMPRSS2 的结合。此外，我们还表明，在蛋白水解切割后，弗林结合的增强会导致异源三聚体的部分从刺突中解离。
