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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.

SUBMITTER: Ali N

PROVIDER: S-EPMC8849831 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Ali Nemat N Khan Rehan R AlAsmari Abdullah F AF Kumar Vijay V

Process biochemistry (Barking, London, England) 20220217

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 pre ...[more]

PMID: 35194375

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Project description:Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes. The spike glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) via its receptor binding domain (RBD) initiating the infection process. Attempting to understand the effect of RBD mutations in VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect the RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of four VOCs (Alpha, Beta, Delta, and Omicron). Our results show that the wt RBD presents two distinct conformations: an "open" conformation where it is free to bind ACE2; and a "closed" conformation, where the RBM ridge blocks the binding surface. The Alpha and Beta variants shift the open/closed equilibrium towards the open conformation by roughly 20%, likely increasing ACE2 binding affinity. Simulations of the Delta and Omicron variants showed extreme results, with the closed conformation being rarely observed. The Delta variant also differed substantially from the other variants, alternating between the open conformation and an alternative "reversed" one, with a significantly changed orientation of the RBM ridge. This alternate conformation could provide a fitness advantage due to increased availability for ACE2 binding, and by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the Omicron and Delta variants, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of Delta, may assist antibody escape.

Dataset Information

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

Publications

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

Similar Datasets

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