Molecular dynamics simulations of the spike trimeric ectodomain of the SARS-CoV-2 Omicron variant: structural relationships with infectivity, evasion to immune system and transmissibility.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron is currently the most prevalent SARS-CoV-2 variant worldwide. Herein, we calculated molecular dynamics simulations of the trimeric spike ^WT and Spike ^BA.1 for 300 ns. Our results show that Spike ^BA.1 has more conformational flexibility than Spike ^WT . Our principal component analysis (PCA) allowed us to observe a broader spectrum of different conformations for Spike ^BA.1 , mainly at N-terminal domain (NTD) and receptor-binding domain (RBD). Such increased flexibility could contribute to decreased neutralizing antibody recognition of this variant. Our molecular dynamics data show that the RBD ^BA.1 easily visits an up-conformational state and the prevalent D614G mutation is pivotal to explain molecular dynamics results for this variant because to lost hydrogen bonding interactions between the residue pairs K854 ^SC /D614 ^SC , Y837 ^MC /D614 ^MC , K835 ^SC /D614 ^SC , T859 ^SC /D614 ^SC . In addition, Spike ^BA.1 residues near the furin cleavage site are more flexible than in Spike ^WT , probably due to P681H and D614G substitutions. Finally, dynamical cross-correlation matrix (DCCM) analysis reveals that D614G and P681H may allosterically affect the cleavage site S1/S2. Conversely, S2' site may be influenced by residues located between NTD and RBD of a neighboring protomer of the Spike ^WT . Such communication may be lost in Spike ^BA.1 , explaining the changes of the cell tropism in the viral infection. In addition, the movements of the NTD ^WT and NTD ^BA.1 may modulate the RBD conformation through allosteric effects. Taken together, our results explain how the structural aspects may explain the observed gains in infectivity, immune system evasion and transmissibility of the Omicron variant.Communicated by Ramaswamy H. Sarma.