In silico investigations of heparin binding to SARS-CoV-2 variants with a focus at the RBD/ACE2 interface.

ABSTRACT

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.