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S373P Mutation Stabilizes the Receptor-Binding Domain of the Spike Protein in Omicron and Promotes Binding
Bin Zheng1, Yuelong Xiao1, Bei Tong2
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210023, China.
Abstract:
A cluster of several newly occurring mutations on Omicron is found at the β-core region of the spike protein's receptor-binding domain (RBD), where mutation rarely happened before. Notably, the binding of SARS-CoV-2 to human receptor ACE2 via RBD happens in a dynamic airway environment, where mechanical force caused by coughing or sneezing occurs. Thus, we used atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS) to measure the stability of RBDs and found that the mechanical stability of Omicron RBD increased by ∼20% compared with the wild type. Molecular dynamics (MD) simulations revealed that Omicron RBD showed more hydrogen bonds in the β-core region due to the closing of the α-helical motif caused primarily by the S373P mutation. In addition to a higher unfolding force, we showed a higher dissociation force between Omicron RBD and ACE2. This work reveals the mechanically stabilizing effect of the conserved mutation S373P for Omicron and the possible evolution trend of the β-core region of RBD.
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