Structural Evolution of Delta (B.1.617.2) and Omicron (BA.1) Spike Glycoproteins

Abstract

The vast amount of epidemiologic and genomic data that were gathered as a global response to the COVID-19 pandemic that was caused by SARS-CoV-2 offer a unique opportunity to shed light on the structural evolution of coronaviruses and in particular on the spike (S) glycoprotein, which mediates virus entry into the host cell by binding to the human ACE2 receptor. Herein, we carry out an investigation into the dynamic properties of the S glycoprotein, focusing on the much more transmissible Delta and Omicron variants. Notwithstanding the great number of mutations that have accumulated, particularly in the Omicron S glycoprotein, our data clearly showed the conservation of some structural and dynamic elements, such as the global motion of the receptor binding domain (RBD). However, our studies also revealed structural and dynamic alterations that were concentrated in the aa 627–635 region, on a small region of the receptor binding motif (aa 483–485), and the so-called “fusion-peptide proximal region”. In particular, these last two S regions are known to be involved in the human receptor ACE2 recognition and membrane fusion. Our structural evidence, therefore, is likely involved in the observed different transmissibility of these S mutants. Finally, we highlighted the role of glycans in the increased RBD flexibility of the monomer in the up conformation of Omicron.

The Spike Mutants Website: A Worldwide Used Resource against SARS-CoV-2

“…Together with the 3D model, through the web portal there is also a short MD trajectory available, 100 ns long, for each analyzed variant. Even though a better understanding of the structural and dynamic perturbation of the system is obtained with longer simulations (see results with one microsecond reported in recent works) [ 34 , 35 , 36 ], we found that interesting features can be inferred by them.…”

“…The 3D protein models of the WT and the mutated spike were initially built by homology modeling using the web tool SWISS-MODEL [ 35 ]. The reference sequence used to align and model the missing atoms of the pre-fusion form of the cryo-EM structure (PDB ID: 6VYB) [ 36 ] was NCBI YP_009724390.1 (UniProt: P0DTC2 SPIKE_SARS2). In this structure, the RBD of the second monomer was in the up conformation, also known as open conformation, which favors the interaction with the ACE2 receptor.…”

D614G and Omicron SARS-CoV-2 variant spike proteins differ in the effects of N-glycan modifications on spike expression, virus infectivity, and neutralization by some therapeutic antibodies

“…Deletion of any of these three glycans favors the RBD down conformation [4,45,46]. Molecular dynamics simulations suggest that the differences in the complex glycanprotein networks between D614G, Delta and Omicron variants can control the flexibility of the RBD domain [47]. The increase in the maximum neutralization observed for the D614G N343Q and N234Q pseudoviruses suggests that a subset of the WT D614G pseudovirus stock that resist neutralization by these antibodies may have glycan modifications at these residues that facilitate evasion of neutralization.…”

RNAi Degrades Spike Protein Gene Transcripts of the SARS-CoV-2 for Developing Drugs to Treat of COVID-19

“…The dynamic properties of the S protein, particularly the much more transmissible Delta and Omicron variants were reported. The more mutations have accumulated in the Omicron S proteins, including the RBD [29,30]. The mutations in the receptorbinding domains (RBDs) of the S protein influence its affinities to ACE2 [31].…”