A 3D structural SARS-CoV-2–human interactome to explore genetic and drug perturbations
Open accessPublished version of a preprint
Abstract
Emergence of new viral agents is driven by evolution of interactions between viral proteins and host targets. For instance, increased infectivity of SARS-CoV-2 compared to SARS-CoV-1 arose in part through rapid evolution along the interface between the spike protein and its human receptor ACE2, leading to increased binding affinity. To facilitate broader exploration of how pathogen-host interactions might impact transmission and virulence in the ongoing COVID-19 pandemic, we performed state-of-the-art interface prediction followed by molecular docking to construct a three-dimensional structural interactome between SARS-CoV-2 and human. We additionally carried out downstream meta-analyses to investigate enrichment of sequence divergence between SARS-CoV-1 and SARS-CoV-2 or human population variants along viral-human protein-interaction interfaces, predict changes in binding affinity by these mutations/variants and further prioritize drug repurposing candidates predicted to competitively bind human targets. We believe this resource ( http://3D-SARS2.yulab.org ) will aid in development and testing of informed hypotheses for SARS-CoV-2 etiology and treatments.
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- Authors
- Wierbowski, S. D., Liang, S., Liu, Y., Chen, Y., Gupta, S., Andre, N. M., Lipkin, S. M., Whittaker, G. R., & Yu, H.
- Affiliations
- Cornell University (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Yu, Haiyuan
- ORCID
- Venue
- Nature Methods
- Published
- 2021-11-29
- Volume
- 18
- Issue
- 12
- Pages
- 1477-1488
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- PMC
- PMC8665054
- OpenAlex
- W3216894362
- Cited by
- 32
- References
- 10
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 8 · 2023: 5 · 2022: 13 · 2021: 1
- FWCI
- 2.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Methods (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01 GM125639, R01 GM124559)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK115398)
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD082568)
- U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (UM1 HG009393)
- National Science Foundation (DBI-1661380)
- Simons Foundation (575547)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- SARS-CoV-2, host-virus protein interaction, protein-protein interfaces, ACE2, spike protein, SARS-CoV-1, sequence divergence, binding affinity, drug repurposing, COVID-19 pandemic, molecular docking, interface prediction
- MeSH terms
- Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Biological Evolution, Humans, Models, Molecular, Protein Conformation, Genetic Variation, Molecular Structure, Virus Attachment, Spike Glycoprotein, Coronavirus
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