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.