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Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

Nash D. Rochman, Guilhem Faure, Yuri I. Wolf, View ORCID ProfilePeter L. Freddolino, Feng Zhang, Eugene V. Koonin
doi: https://doi.org/10.1101/2021.08.30.458225
Nash D. Rochman
1National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD 20894
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  • For correspondence: nash.rochman@nih.gov zhang@broadinstitute.org koonin@ncbi.nlm.nih.gov
Guilhem Faure
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
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Yuri I. Wolf
1National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD 20894
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Peter L. Freddolino
3Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA
4Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
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  • ORCID record for Peter L. Freddolino
Feng Zhang
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
5Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139
6McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139
7Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139
8Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
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  • For correspondence: nash.rochman@nih.gov zhang@broadinstitute.org koonin@ncbi.nlm.nih.gov
Eugene V. Koonin
1National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD 20894
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  • For correspondence: nash.rochman@nih.gov zhang@broadinstitute.org koonin@ncbi.nlm.nih.gov
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Abstract

At the time of this writing, August 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Gamma (417T, 484K, 501Y), and Delta variants (452R, 478K). Overall, epistasis at the RBD surface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. These results suggest that the repertoire of potential escape mutations for the Delta variant is not substantially different from that of the WT, whereas Gamma poses a moderately greater risk for enhanced vaccine escape. Thus, the modest ensemble of mutations relative to the WT shown to reduce vaccine efficacy might constitute the majority of all possible escape mutations.

Significance Potential emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Gamma and Delta variants. The results indicate that emergence of escape mutants is somewhat less likely for the Delta variant than for the wild type and moderately more likely for the Gamma variant. We conclude that the small set of escape-enhancing mutations already identified for the wild type is likely to include the majority of all possible mutations with this effect, a welcome finding.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted August 31, 2021.
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Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape
Nash D. Rochman, Guilhem Faure, Yuri I. Wolf, Peter L. Freddolino, Feng Zhang, Eugene V. Koonin
bioRxiv 2021.08.30.458225; doi: https://doi.org/10.1101/2021.08.30.458225
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Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape
Nash D. Rochman, Guilhem Faure, Yuri I. Wolf, Peter L. Freddolino, Feng Zhang, Eugene V. Koonin
bioRxiv 2021.08.30.458225; doi: https://doi.org/10.1101/2021.08.30.458225

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