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Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces

Joseph H. Lubin, Christopher Markosian, D. Balamurugan, Renata Pasqualini, Wadih Arap, Stephen K. Burley, Sagar D. Khare
doi: https://doi.org/10.1101/2021.12.12.472313
Joseph H. Lubin
1Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
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Christopher Markosian
2Rutgers Cancer Institute of New Jersey, Newark, NJ 07101
3Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103
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D. Balamurugan
4Office of Advanced Research Computing, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
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Renata Pasqualini
2Rutgers Cancer Institute of New Jersey, Newark, NJ 07101
3Division of Cancer Biology, Department of Radiation Oncology, Rutgers New Jersey Medical School, Newark, NJ 07103
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Wadih Arap
2Rutgers Cancer Institute of New Jersey, Newark, NJ 07101
5Division of Hematology/Oncology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103
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Stephen K. Burley
1Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
6RCSB Protein Data Bank, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
7RCSB Protein Data Bank, San Diego Supercomputer Center and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92067
8Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901
9Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
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Sagar D. Khare
1Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
8Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901
9Institute for Quantitative Biomedicine, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
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  • For correspondence: khare@chem.rutgers.edu
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Abstract

There is enormous ongoing interest in characterizing the binding properties of the SARS-CoV-2 Omicron Variant of Concern (VOC) (B.1.1.529), which continues to spread towards potential dominance worldwide. To aid these studies, based on the wealth of available structural information about several SARS-CoV-2 variants in the Protein Data Bank (PDB) and a modeling pipeline we have previously developed for tracking the ongoing global evolution of SARS-CoV-2 proteins, we provide a set of computed structural models (henceforth models) of the Omicron VOC receptor-binding domain (omRBD) bound to its corresponding receptor Angiotensin-Converting Enzyme (ACE2) and a variety of therapeutic entities, including neutralizing and therapeutic antibodies targeting previously-detected viral strains. We generated bound omRBD models using both experimentally-determined structures in the PDB as well as machine learningbased structure predictions as starting points. Examination of ACE2-bound omRBD models reveals an interdigitated multi-residue interaction network formed by omRBD-specific substituted residues (R493, S496, Y501, R498) and ACE2 residues at the interface, which was not present in the original Wuhan-Hu-1 RBD-ACE2 complex. Emergence of this interaction network suggests optimization of a key region of the binding interface, and positive cooperativity among various sites of residue substitutions in omRBD mediating ACE2 binding. Examination of neutralizing antibody complexes for Barnes Class 1 and Class 2 antibodies modeled with omRBD highlights an overall loss of interfacial interactions (with gain of new interactions in rare cases) mediated by substituted residues. Many of these substitutions have previously been found to independently dampen or even ablate antibody binding, and perhaps mediate antibody-mediated neutralization escape (e.g., K417N). We observe little compensation of corresponding interaction loss at interfaces when potential escape substitutions occur in combination. A few selected antibodies (e.g., Barnes Class 3 S309), however, feature largely unaltered or modestly affected protein-protein interfaces. While we stress that only qualitative insights can be obtained directly from our models at this time, we anticipate that they can provide starting points for more detailed and quantitative computational characterization, and, if needed, redesign of monoclonal antibodies for targeting the Omicron VOC Spike protein. In the broader context, the computational pipeline we developed provides a framework for rapidly and efficiently generating retrospective and prospective models for other novel variants of SARS-CoV-2 bound to entities of virological and therapeutic interest, in the setting of a global pandemic.

Competing Interest Statement

R.P. and W.A. are listed as inventors on a patent application related to immunization strategies (International Patent Application no. PCT/US2020/053758, entitled ″Targeted Pulmonary Delivery Compositions and Methods Using Same″). C.M., R.P., and W.A. are inventors on International Patent Application PCT/US2021/040392, filed July 3, 2021, entitled ″Enhancing Immune Responses Through Targeted Antigen Expression″, which describes immunization technology adapted for COVID-19. PhageNova Bio has licensed these intellectual properties and C.M., R.P., and W.A. may be entitled to standard royalties. R.P. and W.A. are founders and equity stockholders of PhageNova Bio. R.P. is Chief Scientific Officer and a paid consultant of PhageNova Bio. R.P. and W.A. are founders and equity shareholders of MBrace Therapeutics; R.P. serves as a paid consultant and member of the Board of Directors for MBrace Therapeutics and W.A. is a Member of the Scientific Advisory Board at MBrace Therapeutics. These arrangements are managed in accordance with the established institutional conflict-of-interest policies of Rutgers, The State University of New Jersey.

Footnotes

  • https://github.com/sagark101/omicron_models

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces
Joseph H. Lubin, Christopher Markosian, D. Balamurugan, Renata Pasqualini, Wadih Arap, Stephen K. Burley, Sagar D. Khare
bioRxiv 2021.12.12.472313; doi: https://doi.org/10.1101/2021.12.12.472313
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Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces
Joseph H. Lubin, Christopher Markosian, D. Balamurugan, Renata Pasqualini, Wadih Arap, Stephen K. Burley, Sagar D. Khare
bioRxiv 2021.12.12.472313; doi: https://doi.org/10.1101/2021.12.12.472313

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