Structural Dynamics of the SARS-CoV-2 Spike Protein: A 2-Year Retrospective Analysis of SARS-CoV-2 Variants (from Alpha to Omicron) Reveals an Early Divergence between Conserved and Variable Epitopes

Abstract

We analyzed the epitope evolution of the spike protein in 1,860,489 SARS-CoV-2 genomes. The structural dynamics of these epitopes was determined by molecular modeling approaches. The D614G mutation, selected in the first months of the pandemic, is still present in currently circulating SARS-CoV-2 strains. This mutation facilitates the conformational change leading to the demasking of the ACE2 binding domain. D614G also abrogated the binding of facilitating antibodies to a linear epitope common to SARS-CoV-1 and SARS-CoV-2. The main neutralizing epitope of the N-terminal domain (NTD) of the spike protein showed extensive structural variability in SARS-CoV-2 variants, especially Delta and Omicron. This epitope is located on the flat surface of the NTD, a large electropositive area which binds to electronegatively charged lipid rafts of host cells. A facilitating epitope located on the lower part of the NTD appeared to be highly conserved among most SARS-CoV-2 variants, which may represent a risk of antibody-dependent enhancement (ADE). Overall, this retrospective analysis revealed an early divergence between conserved (facilitating) and variable (neutralizing) epitopes of the spike protein. These data aid in the designing of new antiviral strategies that could help to control COVID-19 infection by mimicking neutralizing antibodies or by blocking facilitating antibodies.

SARS-CoV-2 quasi-species analysis from patients with persistent nasopharyngeal shedding

“…As a matter of fact, SARS-CoV-2 cellular entry, which is effective thanks to spike protein and ACE2 receptor, can be dramatically changed by a single different nucleotide, the latter changing the entire 3D conformation of the target to its receptor 33 . Moreover, not only can cell biologists now predict the conformational structure of a nucleotide in the spike domain as a result of mutations, but also the viral target-cell receptor affinity resulting from those modifications 34 , which remains extremely sensitive as studies revealed a particular links between Sars-Cov-2 celerity of cellular entry and clinical severity 35 . We strongly encourage teams to involve quasi-species analysis on variant of concern massive surveillance, as we could keep one step ahead fill our quiver with another arrow.…”

SARS-CoV-2 infection of phagocytic immune cells and COVID-19 pathology: Antibody-dependent as well as independent cell entry

“…ADE of coronaviruses can be promoted by antibodies to the spike (S) glycoprotein. This observation was done for SARS-CoV-1 ( 59 , 102 , 157 ) and SARS-CoV-2 ( 127 , 158 ).…”

Evaluation of immune evasion in SARS-CoV-2 Delta and Omicron variants

“…Recent studies on spike protein interactions with monoclonal antibody 4A8 suggests that epitope located within the N- terminal domain of spike is specific site for its binding [7] , [35] . In SARS-CoV-2 mutations, particularly Delta and Omicron, the primary neutralizing epitope of the N-terminal domain (NTD) of the spike protein displayed substantial structural diversity [21] . This epitope is found on the NTD's flat surface, a significant electropositive region that interacts to host cells' electronegatively charged lipid rafts [14] .…”