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Cited by 16Protein Structure and DynamicsEnzyme Structure and FunctionBacteriophages and microbial interactions

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The Viral AlphaFold Database of monomers and homodimers reveals conserved protein folds in viruses of bacteria, archaea, and eukaryotes

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Odai, Roni, Leemann, Michèle, Al-Murad, Tamim, Abdullah, Minhal, Shyrokova, Lena, Tenson, Tanel, Hauryliuk, Vasili, Durairaj, Janani, Pereira, Joana, Atkinson, Gemma C.·2025·Science Advances
DOI 10.1126/sciadv.adz8560PMC PMC12487901

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Abstract

Viruses are the most abundant and genetically diverse entities on Earth, yet the functions and evolution of most viral proteins remain poorly understood. Their rapid evolution often obscures evolutionary relationships, limiting the ability to assign functions using sequence-based methods. Although the conservation of protein fold can reveal deep homologies, viral proteins remain underrepresented in structural databases. We address this by clustering viral sequences from RefSeq and predicting the structures of ~27,000 representative proteins using AlphaFold2 to create the Viral AlphaFold Database (VAD). We uncover conserved folds in diverse viruses infecting bacteria, archaea, and eukaryotes. We predict homodimers and make comparisons to the Protein Data Bank, providing data on oligomerization potential. We reveal considerable functional darkness in the viral protein universe and report the discovery and validation of an uncharacterized toxin-antitoxin system. The VAD provides a foundation for exploring viral structure-function relationships, including ancient folds shaping viral interactions across all life.

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Metadata

Authors
Odai, R., Leemann, M., Al-Murad, T., Abdullah, M., Shyrokova, L., Tenson, T., Hauryliuk, V., Durairaj, J., Pereira, J., & Atkinson, G. C.
Affiliations
  • Lund University (SE)
  • University of Basel (CH)
  • University of Tartu (EE)
  • SIB Swiss Institute of Bioinformatics (CH)
Corresponding author
Atkinson, Gemma C.
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-10-03
Volume
11
Issue
40
Pages
eadz8560-eadz8560
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adz8560
PMC
PMC12487901
OpenAlex
W4414694698
Cited by
16
References
6
Citations by year
2026: 9 · 2025: 7
FWCI
4.78
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Lirias (KU Leuven) (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Universität Basel
  • Göran Gustafssons Stiftelser
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (223634)
  • Eesti Teadusagentuur (PRG2696)
  • Knut och Alice Wallenbergs Stiftelse (2022-06725, 2020.0037)
  • Vetenskapsrådet (2021-01146, 2019-01085, 2024-06071, 2024-06059, 2022-01603, 2022-06725)
  • Erasmus+
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
Keywords
viral proteins, protein structure prediction, AlphaFold2, homodimer, oligomerization, viral evolution, toxin-antitoxin systems, archaeal viruses, eukaryotic viruses, structure-function relationship, protein sequence clustering
MeSH terms
Archaea, Bacteria, Models, Molecular, Viral Proteins, Viruses, Protein Folding, Databases, Protein, Protein Multimerization, Eukaryota

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