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Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain.
Comput Biol Med. 2022 Oct; 149:106035.CB

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 variant (Omicron), represents a significant deviation in genetic makeup and function compared to previous variants. Following the BA.1 sublineage, the BA.2 and BA.3 Omicron subvariants became dominant, and currently the BA.4 and BA.5, which are quite distinct variants, have emerged. Using molecular dynamics simulations, we investigated the binding characteristics of the Delta and Omicron (BA.1) variants in comparison to wild-type (WT) at the interface of the spike protein receptor binding domain (RBD) and human angiotensin converting enzyme-2 (ACE2) ectodomain. The primary aim was to compare our molecular modelling systems with previously published observations, to determine the robustness of our approach for rapid prediction of emerging future variants. Delta and Omicron were found to bind to ACE2 with similar affinities (-39.4 and -43.3 kcal/mol, respectively) and stronger than WT (-33.5 kcal/mol). In line with previously published observations, the energy contributions of the non-mutated residues at the interface were largely retained between WT and the variants, with F456, F486, and Y489 having the strongest energy contributions to ACE2 binding. Further, residues N440K, Q498R, and N501Y were predicted to be energetically favourable in Omicron. In contrast to Omicron, which had the E484A and K417N mutations, intermolecular bonds were detected for the residue pairs E484:K31 and K417:D30 in WT and Delta, in accordance with previously published findings. Overall, our simplified molecular modelling approach represents a step towards predictive model systems for rapidly analysing arising variants of concern.

Authors+Show Affiliations

Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia; School of Science, STEM College, RMIT University, VIC, 3001, Australia.Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia; School of Science, STEM College, RMIT University, VIC, 3001, Australia.Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3052, Australia.School of Science, STEM College, RMIT University, VIC, 3001, Australia.Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3052, Australia. Electronic address: karat@unimelb.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

36055162

Citation

Pitsillou, Eleni, et al. "Molecular Dynamics Simulations Highlight the Altered Binding Landscape at the spike-ACE2 Interface Between the Delta and Omicron Variants Compared to the SARS-CoV-2 Original Strain." Computers in Biology and Medicine, vol. 149, 2022, p. 106035.
Pitsillou E, Liang JJ, Beh RC, et al. Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain. Comput Biol Med. 2022;149:106035.
Pitsillou, E., Liang, J. J., Beh, R. C., Hung, A., & Karagiannis, T. C. (2022). Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain. Computers in Biology and Medicine, 149, 106035. https://doi.org/10.1016/j.compbiomed.2022.106035
Pitsillou E, et al. Molecular Dynamics Simulations Highlight the Altered Binding Landscape at the spike-ACE2 Interface Between the Delta and Omicron Variants Compared to the SARS-CoV-2 Original Strain. Comput Biol Med. 2022;149:106035. PubMed PMID: 36055162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular dynamics simulations highlight the altered binding landscape at the spike-ACE2 interface between the Delta and Omicron variants compared to the SARS-CoV-2 original strain. AU - Pitsillou,Eleni, AU - Liang,Julia J, AU - Beh,Raymond C, AU - Hung,Andrew, AU - Karagiannis,Tom C, Y1 - 2022/08/27/ PY - 2022/4/1/received PY - 2022/8/15/revised PY - 2022/8/20/accepted PY - 2022/9/3/pubmed PY - 2022/9/24/medline PY - 2022/9/2/entrez KW - ACE2 receptors KW - Delta variant KW - Omicron variant KW - SARS-CoV-2 KW - Spike protein SP - 106035 EP - 106035 JF - Computers in biology and medicine JO - Comput Biol Med VL - 149 N2 - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 variant (Omicron), represents a significant deviation in genetic makeup and function compared to previous variants. Following the BA.1 sublineage, the BA.2 and BA.3 Omicron subvariants became dominant, and currently the BA.4 and BA.5, which are quite distinct variants, have emerged. Using molecular dynamics simulations, we investigated the binding characteristics of the Delta and Omicron (BA.1) variants in comparison to wild-type (WT) at the interface of the spike protein receptor binding domain (RBD) and human angiotensin converting enzyme-2 (ACE2) ectodomain. The primary aim was to compare our molecular modelling systems with previously published observations, to determine the robustness of our approach for rapid prediction of emerging future variants. Delta and Omicron were found to bind to ACE2 with similar affinities (-39.4 and -43.3 kcal/mol, respectively) and stronger than WT (-33.5 kcal/mol). In line with previously published observations, the energy contributions of the non-mutated residues at the interface were largely retained between WT and the variants, with F456, F486, and Y489 having the strongest energy contributions to ACE2 binding. Further, residues N440K, Q498R, and N501Y were predicted to be energetically favourable in Omicron. In contrast to Omicron, which had the E484A and K417N mutations, intermolecular bonds were detected for the residue pairs E484:K31 and K417:D30 in WT and Delta, in accordance with previously published findings. Overall, our simplified molecular modelling approach represents a step towards predictive model systems for rapidly analysing arising variants of concern. SN - 1879-0534 UR - https://www.unboundmedicine.com/medline/citation/36055162/Molecular_dynamics_simulations_highlight_the_altered_binding_landscape_at_the_spike_ACE2_interface_between_the_Delta_and_Omicron_variants_compared_to_the_SARS_CoV_2_original_strain_ DB - PRIME DP - Unbound Medicine ER -