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The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested by In Silico Study.
Int J Mol Sci. 2022 Nov 04; 23(21)IJ

Abstract

SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 variants differ in transmissibility and pathogenicity in the human population, although the molecular basis for this difference is still debatable. A significant role is attributed to amino acid changes in the binding surface of the Spike protein to the ACE2 receptor, which may facilitate virus entry into the cell or contribute to immune evasion. We modeled in silico the interaction between Spike RBDs of Wuhan-Hu-1, Delta, and Omicron BA.1 variants and ACE2 at different pHs (pH 5 and pH 7) and showed that the strength of this interaction was higher for the Omicron BA.1 RBD compared to Wuhan-Hu-1 or Delta RBDs and that the effect was more profound at pH 5. This finding is strikingly related to the increased ability of Omicron variants to spread in the population. We also noted that during its spread in the population, SARS-CoV-2 evolved to a more charged, basic composition. We hypothesize that the more basic surface of the Omicron variant may facilitate its spread in the upper respiratory tract but not in the lower respiratory tract, where pH estimates are different. We calculated the amyloidogenic properties of Spike RBDs in different SARS-CoV-2 variants and found eight amyloidogenic regions in the Spike RBDs for each of the variants predicted by the FoldAmyloid program. Although all eight regions were almost identical in the Wuhan to Gamma variants, two of them were significantly longer in both Omicron variants, making the Omicron RBD more amyloidogenic. We discuss how the increased predicted amyloidogenicity of the Omicron variants RBDs may be important for protein stability, influence its interaction with ACE2 and contribute to immune evasion.

Authors+Show Affiliations

Laboratory of Amyloid Biology, St. Petersburg State University, 199034 St. Petersburg, Russia.Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia. Institute of Mathematical Problems of Biology RAS, The Branch of Keldysh Institute of Applied Mathematics, Russian Academy of Sciences, 142290 Pushchino, Russia.Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia. Institute of Environmental and Agricultural Biology (X-BIO), Tyumen State University, 625003 Tyumen, Russia.Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

36362302

Citation

Aksenova, Anna Y., et al. "The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested By in Silico Study." International Journal of Molecular Sciences, vol. 23, no. 21, 2022.
Aksenova AY, Likhachev IV, Grishin SY, et al. The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested by In Silico Study. Int J Mol Sci. 2022;23(21).
Aksenova, A. Y., Likhachev, I. V., Grishin, S. Y., & Galzitskaya, O. V. (2022). The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested by In Silico Study. International Journal of Molecular Sciences, 23(21). https://doi.org/10.3390/ijms232113502
Aksenova AY, et al. The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested By in Silico Study. Int J Mol Sci. 2022 Nov 4;23(21) PubMed PMID: 36362302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested by In Silico Study. AU - Aksenova,Anna Y, AU - Likhachev,Ilya V, AU - Grishin,Sergei Y, AU - Galzitskaya,Oxana V, Y1 - 2022/11/04/ PY - 2022/08/08/received PY - 2022/10/19/revised PY - 2022/11/01/accepted PY - 2022/11/11/entrez PY - 2022/11/12/pubmed PY - 2022/11/15/medline KW - Omicron KW - RBD KW - SARS-CoV-2 KW - Spike KW - amyloidogenic properties KW - molecular modeling JF - International journal of molecular sciences JO - Int J Mol Sci VL - 23 IS - 21 N2 - SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 variants differ in transmissibility and pathogenicity in the human population, although the molecular basis for this difference is still debatable. A significant role is attributed to amino acid changes in the binding surface of the Spike protein to the ACE2 receptor, which may facilitate virus entry into the cell or contribute to immune evasion. We modeled in silico the interaction between Spike RBDs of Wuhan-Hu-1, Delta, and Omicron BA.1 variants and ACE2 at different pHs (pH 5 and pH 7) and showed that the strength of this interaction was higher for the Omicron BA.1 RBD compared to Wuhan-Hu-1 or Delta RBDs and that the effect was more profound at pH 5. This finding is strikingly related to the increased ability of Omicron variants to spread in the population. We also noted that during its spread in the population, SARS-CoV-2 evolved to a more charged, basic composition. We hypothesize that the more basic surface of the Omicron variant may facilitate its spread in the upper respiratory tract but not in the lower respiratory tract, where pH estimates are different. We calculated the amyloidogenic properties of Spike RBDs in different SARS-CoV-2 variants and found eight amyloidogenic regions in the Spike RBDs for each of the variants predicted by the FoldAmyloid program. Although all eight regions were almost identical in the Wuhan to Gamma variants, two of them were significantly longer in both Omicron variants, making the Omicron RBD more amyloidogenic. We discuss how the increased predicted amyloidogenicity of the Omicron variants RBDs may be important for protein stability, influence its interaction with ACE2 and contribute to immune evasion. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/36362302/The_Increased_Amyloidogenicity_of_Spike_RBD_and_pH_Dependent_Binding_to_ACE2_May_Contribute_to_the_Transmissibility_and_Pathogenic_Properties_of_SARS_CoV_2_Omicron_as_Suggested_by_In_Silico_Study_ DB - PRIME DP - Unbound Medicine ER -