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Cited by 20Protein Structure and DynamicsSARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approaches

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A general computational design strategy for stabilizing viral class I fusion proteins

Open access
Gonzalez, Karen J., Huang, Jiachen, Criado, Miria F., Banerjee, Avik, Tompkins, Stephen M., Mousa, Jarrod J., Strauch, Eva-Maria·2024·Nature Communications
DOI 10.1038/s41467-024-45480-zPMC PMC10864359

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Abstract

Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a handful of designs. The solved structures of these designed proteins from all three viruses evidence the atomic accuracy of our approach. Furthermore, the humoral response of the redesigned RSV F protein compares to that of the recently approved vaccine in a mouse model. While the parallel design of two conformations allows the identification of energetically sub-optimal positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.

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Metadata

Authors
Gonzalez, K. J., Huang, J., Criado, M. F., Banerjee, A., Tompkins, S. M., Mousa, J. J., & Strauch, E.-M.
Affiliations
University of Georgia (US)
Corresponding author
Strauch, Eva-Maria
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-02-13
Volume
15
Issue
1
Pages
1335-1335
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-45480-z
PMC
PMC10864359
OpenAlex
W4391776152
Cited by
20
References
8
Citations by year
2026: 10 · 2025: 6 · 2024: 3
FWCI
2.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI140245)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
class I fusion proteins, computational protein design, RSV F protein, human metapneumovirus, SARS-CoV-2 spike protein, vaccine immunogens, humoral immune response, viral fusion, conformational change

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