Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain
The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2023
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| Online Access: | https://hdl.handle.net/1721.1/147927 |
| _version_ | 1826199247622504448 |
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| author | Miller, Nathaniel L Clark, Thomas Raman, Rahul Sasisekharan, Ram |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Miller, Nathaniel L Clark, Thomas Raman, Rahul Sasisekharan, Ram |
| author_sort | Miller, Nathaniel L |
| collection | MIT |
| description | The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBDdown-RBDdown interface. |
| first_indexed | 2024-09-23T11:17:02Z |
| format | Article |
| id | mit-1721.1/147927 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:17:02Z |
| publishDate | 2023 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1479272023-02-08T03:31:29Z Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain Miller, Nathaniel L Clark, Thomas Raman, Rahul Sasisekharan, Ram Massachusetts Institute of Technology. Department of Biological Engineering The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBDdown-RBDdown interface. 2023-02-07T14:08:01Z 2023-02-07T14:08:01Z 2022 2023-02-07T13:58:29Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147927 Miller, Nathaniel L, Clark, Thomas, Raman, Rahul and Sasisekharan, Ram. 2022. "Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain." Cell Reports Medicine, 3 (2). en 10.1016/J.XCRM.2022.100527 Cell Reports Medicine Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Cell Reports |
| spellingShingle | Miller, Nathaniel L Clark, Thomas Raman, Rahul Sasisekharan, Ram Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain |
| title | Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain |
| title_full | Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain |
| title_fullStr | Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain |
| title_full_unstemmed | Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain |
| title_short | Insights on the mutational landscape of the SARS-CoV-2 Omicron variant receptor-binding domain |
| title_sort | insights on the mutational landscape of the sars cov 2 omicron variant receptor binding domain |
| url | https://hdl.handle.net/1721.1/147927 |
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