Conformational Changes of the Receptor Binding Domain of SARS-CoV-2 Spike Protein and Prediction of a B-Cell Antigenic Epitope Using Structural Data

Abstract

COVID-19, the illness caused by the SARS-CoV-2 virus, is now a worldwide pandemic with mortality in hundreds of thousands as infections continue to increase. Containing the spread of this viral infection and decreasing the mortality rate is a major challenge. Identifying appropriate antigenic epitopes from the viral proteins is a very important task for vaccine production and the development of diagnostic kits and antibody therapy. A novel antigenic epitope would be specific to the SARS-CoV-2 virus and can distinguish infections caused by common cold viruses. In this study two approaches are employed to identify both continuous and conformational B-cell antigenic epitopes. To achieve this goal, we modeled a complete structure of the receptor binding domain (RBD) of the spike protein using recently deposited coordinates (6vxx, 6vsb, and 6w41) in the protein data bank. In addition, we also modeled the RBD-ACE2 receptor complex for SARS-CoV-2 using the SARS-CoV RBD-ACE2 complex (3D0J) as a reference model. Finally, structure based predicted antigenic epitopes were compared to the ACE2 binding region of RBD of SARS-CoV-2. The identified conformational epitopes show overlaps with the ACE2-receptor binding region of the RBD of SARS-CoV-2. Strategies defined in the current study identified novel antigenic epitope that is specific to the SARS-CoV-2 virus. Integrating such approach in the diagnosis can distinguish infections caused by common cold viruses from SARS-CoV-2 virus.

Emergence of SARS-CoV-2 Variants in the World: How Could This Happen?

“…This structure binds to the host cell receptor, angiotensin-converting enzyme 2 (ACE2), allowing the virus to enter the cell. In addition, RBD includes a receptor-binding motif (RBM), which contains amino acid residues that directly contact ACE2 [30,31]. The S2 subunit includes the fusion peptide (FP), 2 heptad repeat (HR1 and HR2) subdomains, a transmembrane helix, and a cytoplasmic tail.…”

An Electrostatically-steered Conformational Selection Mechanism Promotes SARS-CoV-2 Spike Protein Variation

“…Therefore, considering the key observation of the global increase in hydrophobicity across the selected substitutions, we asked what these mutations could bring on a structural level. We constructed 475 structural models of S protein corresponding to all 148 substitutions in 4 known conformational states which are involved in the recognition, namely unbound (“closed” 66 , 67 ( N =148), “open” 66 , 67 ( N =148)), bound [68] ( N =148) and postfusion [39] ( N =31) ( Figure1 (a-d) ). As a control, the Wuhan strain S protein was included.…”

Structural Insights on the SARS-CoV-2 Variants of Concern Spike Glycoprotein: A Computational Study With Possible Clinical Implications

“…In fact, it was found that viral epitopes (such as Influenza and CMV) that lack sequence identity with SARS2 are able to stimulate an immune response (Mahajan et al, 2021) which we believe is attributable to similar protein structural formation. In this regard, we postulate that high VOC S1-CTD and S1-NTD structural similarity (TM > 0.70) with either the original SARS2 or endemic HCoV could putatively have crossreactivity with the original SARS2 and endemic HCoV spike models (Ladner et al, 2021) possibly ascribable to having multiple similar conformational epitopes that are considered valuable in neutralizing viral pathogenesis (Khare et al, 2021). This is consistent with previous work showing that T cell frequencies against the original SARS2 have likewise been correlated to VOC (Stankov et al, 2021) which we suspect to be due to structural similarity (particularly S1-CTD).…”

“…Moreover, VOC have been shown to partially escape humoral immune response, however, VOC are found to be unable to escape cellular immune response among convalescent donors and vaccinees (Geers et al, 2021). This would highlight the putative significance of cellular immune response [particularly Th1 and Tfh cells (Poland et al, 2020) ] in providing lasting protection against VOC and, more importantly, the T cell-recognizing conformational epitopes that can counteract viral infectivity (Khare et al, 2021).…”