Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1)

Abstract

Herein, we simulated the trimeric Spike of the variants B.1.617.2, BA.2, BA.5 and BQ.1 for 300 ns. We derived mechanisms by which the substitutions K417N, L452R, N444T and N460K may favor resistance to neutralizing antibodies. The K417N and L452R contribute to the expansion of the networks of hydrogen bonding interactions with neighboring residues, decreasing their capacity to interact with neutralizing antibodies. The SpikeBQ.1 possesses two unique K444T and N460K mutations that expand the network of hydrogen bonding interactions. This lysine also contributes one novel strong saline interaction and both substitutions may favor resistance to neutralizing antibodies. We also investigated how the substitutions D614G, P681R, and P681H impact Spike structural conformations and discuss the impact of these changes to infectivity and lethality. The prevalent D614G substitution plays a key role in the communication between the glycine and the residues of a {beta}-strand located between the NTD and the RBD, impacting the transition between up- and down-RBD states. The P681R mutation, found in the Delta variant, favors intra- and inter-protomer correlations between the subunits S1 and S2. Conversely, in Omicron sub-variants, P681H decreases the intra- and inter-protomer long-range interactions within the trimeric Spike, providing an explanation for the reduced fusogenicity of this variant. Taken together, our results enhance the knowledge on how novel mutations lead to changes in infectivity and reveal mechanisms by which SARS-CoV-2 may evade the immune system.