Ali Nemat, Khan Rehan, AlAsmari Abdullah F, Kumar Vijay
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O.Box 55760, Riyadh 11451, Saudi Arabia.
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Process Biochem. 2022 Apr;115:70-79. doi: 10.1016/j.procbio.2022.02.012. Epub 2022 Feb 17.
The increased infectivity and transmissibility of SARS-CoV-2 new variants were contributed largely by increase binding of receptor binding domain (RBD) domain of the Spike (S) protein to its cellular receptor ACE2 (Angiotensin-Converting Enzyme 2). Several studies have indicated that heparin and its derivatives interact to SARS-CoV-2 S-RBD and inhibits the binding of ACE2 which blocks the viral invasion. However, it is largely unclear how these SARS-CoV-2 variants affects ACE2 binding in the presence of heparin. Herein, using the molecular docking and interaction energy analysis, we showed that N501Y, L452R-E484Q, and E484K mutations bind strongly with heparin in the range of - 7.4 to - 8.0 kcal/mol. The triple mutations, K417N-E484K-N501Y, and K417T-E484K-N501Y displayed weaker binding affinity to heparin (-6.6 kcal/mol). Further, we showed that most of the RBD mutations increased the binding affinity of ACE2 in the absence of heparin, with the maximum increase observed for N501Y (-13.7 kcal/mol). Also, in the presence of heparin, ACE2 binds strongly to the mutant RBD as compared to WT RBD. The strong RBD/ACE2 interaction was observed in case of triple variants (-11.3 kcal/mol) whereas, N501Y showed weakest binding of RBD/ACE2 in the presence of heparin (-9.2 kcal/mol). The strong binding of ACE2 to RBD-heparin complex in these variants will leads to strong inhibition of their entry into host cells.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）新变种传染性和传播性的增加，很大程度上是由于刺突（S）蛋白的受体结合域（RBD）与细胞受体血管紧张素转换酶2（ACE2）的结合增加所致。多项研究表明，肝素及其衍生物可与SARS-CoV-2的S-RBD相互作用，并抑制ACE2的结合，从而阻断病毒入侵。然而，在肝素存在的情况下，这些SARS-CoV-2变种如何影响ACE2的结合，目前尚不清楚。在此，我们通过分子对接和相互作用能分析表明，N50IY、L452R-E484Q和E484K突变与肝素的结合力很强，范围在-7.4至-8.0千卡/摩尔之间。三重突变K417N-E484K-N501Y和K417T-E484K-N501Y对肝素的结合亲和力较弱（-6.6千卡/摩尔）。此外，我们还表明，在没有肝素的情况下，大多数RBD突变增加了ACE2的结合亲和力，其中N501Y增加最多（-13.7千卡/摩尔）。而且，在肝素存在的情况下，与野生型RBD相比，ACE2与突变型RBD的结合更强。在三重变种的情况下观察到很强的RBD/ACE2相互作用（-11.3千卡/摩尔），而在肝素存在的情况下，N501Y的RBD/ACE2结合最弱（-9.2千卡/摩尔）。这些变种中ACE2与RBD-肝素复合物的强结合将导致其进入宿主细胞受到强烈抑制。
