Omicron’s Spike Receptor-Binding Domain Mutations Significantly Stabilize its Conformational State

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Abstract The Omicron variant and its sub lineages are the only current circulating SARS-CoV-2 viruses world-wide. In this study, the conformational stability of the isolated Receptor Binding Domain (RBD) of the virus’s spike protein, which has been used for highly successful vaccines (Ref. 12), is examined in detail. The conformational stability of Omicron’s RBD over the Wild-type (WT) strain is shown to be greatly increased and traceable to just a few mutations: K417N, S373P, E484A. The mutation S373P,which is shown to represent a significant beta strand enhancement within the receptor binding domain, has been previously identified through atomic force microscopy (Ref. 19) as critical to the increased biomechanical stability of the Omicron variant. Here it is demonstrated that these stabilizing mutations significantly increase the internal energy of the RBD, which is specifically associated with its β hairpin loop domain interactions (intra-loop and loop-RBD interactions). These internal energy increases are traced to the formation of new hydrogens bonds between non-mutated RBD residues that are brought closer together in the more stable Omicron structure. Furthermore, the enhanced stability of the isolated Omicron receptor binding domain over WT results in its configurational alignment with the RBD bound state conformation to its binding partner (human) Angiotensin Converting Enzyme II. The bound state conformation of the RBD is shown to be nearly identical across WT and Omicron variants. This suggests that a dynamic, energetic analysis of protein bound and unbound state conformations may potentially provide a general “road map” for site directed mutational stabilizing of proteins as antigens for vaccines.

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