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)

Herein, we conducted simulations of trimeric Spike from several SARS-CoV-2 variants of concern (Delta and Omicron sub-variants BA.2, BA.5, and BQ.1) and investigated the mechanisms by which specific mutations confer resistance to neutralizing antibodies. We observed that the mutations primarily affect the cooperation between protein domains within and between protomers. The substitutions K417N and L452R expand hydrogen bonding interactions, reducing their interaction with neutralizing antibodies. By interacting with nearby residues, the K444T and N460K mutations in the Spike^BQ.1 variant potentially reduces solvent exposure, thereby promoting resistance to antibodies. We also examined the impact of D614G, P681R, and P681H substitutions on Spike protein structure that may be related to infectivity. The D614G substitution influences communication between a glycine residue and neighboring domains, affecting the transition between up- and -down RBD states. The P681R mutation, found in the Delta variant, enhances correlations between protein subunits, while the P681H mutation in Omicron sub-variants weakens long-range interactions that may be associated with reduced fusogenicity. Using a multiple linear regression model, we established a connection between inter-protomer communication and loss of sensitivity to neutralizing antibodies. Our findings underscore the importance of structural communication between protein domains and provide insights into potential mechanisms of immune evasion by SARS-CoV-2. Overall, this study deepens our understanding of how specific mutations impact SARS-CoV-2 infectivity and shed light on how the virus evades the immune system.

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