PT  - JOURNAL ARTICLE
AU  - Bin Zheng
AU  - Yuelong Xiao
AU  - Bei Tong
AU  - Yutong Mao
AU  - Rui Ge
AU  - Fang Tian
AU  - Xianchi Dong
AU  - Peng Zheng
TI  - S373P Mutation of Spike Protein in SARS-CoV-2 Stabilizes Omicron
AID  - 10.1101/2022.06.22.497114
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.22.497114
4099  - http://biorxiv.org/content/early/2022/06/23/2022.06.22.497114.short
4100  - http://biorxiv.org/content/early/2022/06/23/2022.06.22.497114.full
AB  - Recently, a cluster of several newly occurring mutations on Omicron, which is currently the dominant SARS-CoV-2 variant, are found at the (mechanically) stable β-core region of 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 and applies to the proteins. Thus, we used atomic force microscopy-based single-molecule force spectroscopy (AFM-SMFS) to measure the stability of RBDs and found that the unfolding force of Omicron RBD increased by 20% compared with the wild-type. Molecular dynamics 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, which was further confirmed by the experiment. This work reveals the stabilizing effect of the S373P mutation and suggests mechanical stability becomes another important factor in SARS-CoV-2 mutation selection.Competing Interest StatementThe authors have declared no competing interest.