Conformational dynamics and allosteric modulation of the SARS-CoV-2 spike

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells through binding to angiotensin-converting enzyme 2 (ACE2). This interaction is mediated by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Structural and dynamic data have shown that S can adopt multiple conformations, which controls the exposure of the ACE2-binding site in the RBD. Here, using single-molecule Förster resonance energy transfer (smFRET) imaging we report the effects of ACE2 and antibody binding on the conformational dynamics of S from the Wuhan-1 strain and in the presence of the D614G mutation. We find that D614G modulates the energetics of the RBD position in a manner similar to ACE2 binding. We also find that antibodies that target diverse epitopes, including those distal to the RBD, stabilize the RBD in a position competent for ACE2 binding. Parallel solution-based binding experiments using fluorescence correlation spectroscopy (FCS) indicate antibody-mediated enhancement of ACE2 binding. These findings inform on novel strategies for therapeutic antibody cocktails.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Marco A Diaz-Salinas

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.
Qi Li

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States

Competing interests
Qi Li, A patent application has been filed on May 5, 2020 on monoclonal antibodies targeting SARS-CoV-2 (U.S. Patent and Trademark Office patent application no. 63/020,483; patent applicants: YW, ME, and QL.
Monir Ejemel

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States

Competing interests
Monir Ejemel, A patent application has been filed on May 5, 2020 on monoclonal antibodies targeting SARS-CoV-2 (U.S. Patent and Trademark Office patent application no. 63/020,483; patent applicants: YW, ME, and QL.
Leonid Yurkovetskiy

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.
Jeremy Luban

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5650-4054
Kuang Shen

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.
Yang Wang

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States

Competing interests
Yang Wang, A patent application has been filed on May 5, 2020 on monoclonal antibodies targeting SARS-CoV-2 (U.S. Patent and Trademark Office patent application no. 63/020,483; patent applicants: YW, ME, and QL.
James B Munro

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States

For correspondence
james.munro@umassmed.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7634-4633

Funding

UMass Chan Medical School COVID-19 Pandemic Relief Fund

James B Munro

National Institutes of Health (R37AI147868)

Jeremy Luban

National Institutes of Health (R01AI148784)

Jeremy Luban
James B Munro

National Institutes of Health (K22CA241362)

Kuang Shen

Evergrande COVID-19 Response Fund

Jeremy Luban

Massachusetts Consortium on Pathogen Readiness

Jeremy Luban

Worcester Foundation for Biomedical Research

Kuang Shen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.