SARS-CoV-2 variant surge and vaccine breakthrough infection: A computational analysis.

Coronavirus Delta variant was first detected in India in October of 2020, and it led to a massive second wave of COVID-19 cases in the country. Since then, the highly infectious Delta strain has been spreading globally. The Delta variant and its sub-lineages showed an increased infection rate with a reduced effect of the potential antibody neutralization. The current work is a modeled computational analysis of the mutated receptor-binding domain (RBD) of the SARS-CoV-2 B.1.617 lineage binding with ACE2 and GRP78 to understand the increased strain transmissibility. The cell-surface Glucose Regulated Protein 78 (GRP78) attached to the mutated ACE2-SARS-CoV-2 Spike RBD complex is modeled. The results showed that GRP78 β-substrate-binding domain weakly binds to the wild-type RBD combined with angiotensin-converting enzyme 2 (ACE2) within the SARS-CoV-2 Spike RBD-ACE2 complex. Both GRP78 and ACE2 bind approximately in the same region on the wild-type SARS-CoV-2 Spike RBD surface. On the other hand, GRP78 strongly binds to the mutated SARS-CoV-2 Spike RBD in the RBD-ACE2 complex through the α-substrate-binding domain instead of β-substrate-binding domain in a different region from that of ACE2. The current findings suggest that blocking the main ACE2 pathway may not prevent the interactions between GRP78 and the mutated SARS-CoV-2 Spike RBD, which might introduce an additional avenue into the virus invasion for the host cell if the ACE2 pathway is blocked by the neutralized antibodies. Hence, the peptide satpdb10668 has been proposed as a potential inhibitor of SARS-CoV-2 attachment and virus invasion into the host cell.