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Origin of the tight binding mode to ACE2 triggered by multi-point mutations in the omicron variant: a dynamic insight.
Zhao, Xiaoyu; Xiong, Danyang; Luo, Song; Duan, Lili.
  • Zhao X; School of Physics and Electronics, Shandong Normal University, Jinan, 250014, China. duanll@sdnu.edu.cn.
  • Xiong D; School of Physics and Electronics, Shandong Normal University, Jinan, 250014, China. duanll@sdnu.edu.cn.
  • Luo S; School of Physics and Electronics, Shandong Normal University, Jinan, 250014, China. duanll@sdnu.edu.cn.
  • Duan L; School of Physics and Electronics, Shandong Normal University, Jinan, 250014, China. duanll@sdnu.edu.cn.
Phys Chem Chem Phys ; 24(15): 8724-8737, 2022 Apr 13.
Article in English | MEDLINE | ID: covidwho-1774006
ABSTRACT
The continuous spread of the newly emerged SARS-CoV-2 Omicron variant (B.1.1.529) has become an important reason for the surge in COVID-19 infections. Its numerous mutated residues containing key sites on the receptor-binding domain (RBD) undoubtedly pose new challenges for epidemic control. Although the preventive measures are becoming more sophisticated, the effects of mutations on the binding of the virus to the receptor protein remain to be elucidated. Here, we used molecular dynamics (MD) simulations to investigate the differences in the binding mode between the Omicron variant and the angiotensin-converting enzyme 2 (ACE2) compared to the wild-type strain (WT). Multi-point mutations in the Omicron variant RBD could cause the conformation shift in the large Loop (where T478K and E484A are located), which makes it easier to wrap the N-terminal helix of ACE2 and form tighter contacts. The stronger electrostatic interaction was the main reason for its enhanced binding affinity as compared to WT. This was due to the large number of positively charged patches (N440K, T478K, Q493R, Q498R, and Y505H) formed by the substitution of neutral amino acids at multiple sites. The appearance of these highly polar hydrophilic amino acids may cause local perturbations and affect the electrostatic complementarity of RBD with the ACE2, and further mediate conformational changes. Thus, a more extensive interaction network was found in the mutation system and the complex interaction cluster was formed near E37@ACE2, which was essential for the stable binding of the two. In addition, we speculated that these mutations may affect the electrostatic complementarity with the four potential antibodies to reduce the sensitivity of the virus to antibodies. This study reveals the key details of the Omicron variant binding to ACE2 and provides important theoretical views for the enhanced infectivity of this variant. We hope that these observations can provide timely molecular insights for responding to the Omicron variant pandemic.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Type of study: Observational study / Prognostic study Topics: Variants Limits: Humans Language: English Journal: Phys Chem Chem Phys Journal subject: Biophysics / Chemistry Year: 2022 Document Type: Article Affiliation country: D2cp00449f

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Type of study: Observational study / Prognostic study Topics: Variants Limits: Humans Language: English Journal: Phys Chem Chem Phys Journal subject: Biophysics / Chemistry Year: 2022 Document Type: Article Affiliation country: D2cp00449f