Protein structure-informed bacteriophage genome annotation with Phold
Open accessPublished version of a preprint
Abstract
Bacteriophage (phage) genome annotation is essential for understanding their functional potential and suitability for use as therapeutic agents. Here, we introduce Phold, an annotation framework utilizing protein structural information that combines the ProstT5 protein language model and structural alignment tool Foldseek. Phold assigns annotations using a database of over 1.36 million predicted phage protein structures with high-quality functional labels. Benchmarking reveals that Phold outperforms existing sequence-based homology approaches in functional annotation sensitivity whilst maintaining speed, consistency, and scalability. Applying Phold to diverse cultured and metagenomic phage genomes shows it consistently annotates over 50% of genes on an average phage and 40% on an average archaeal virus. Comparisons of phage protein structures to other protein structures across the tree of life reveal that phage proteins commonly have structural homology to proteins shared across the tree of life, particularly those that have nucleic acid metabolism and enzymatic functions. Phold is available as free and open-source software at https://github.com/gbouras13/phold.
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Cites
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Self-citationColabFold - Making protein folding accessible to all
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“2893 of these proteins had structure predictions already in the AlphaFold database v4 [ 51 ], which were down-loaded.”
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- Authors
- Bouras, G., Grigson, S. R., Mirdita, M., Heinzinger, M., Papudeshi, B., Mallawaarachchi, V., Green, R., Kim, R. S., Mihalia, V., Psaltis, A. J., Wormald, P.-J., Vreugde, S., Steinegger, M., & Edwards, R. A.
- Affiliations
- Central Adelaide Local Health Network (AU)
- Flinders University (AU)
- Seoul National University (KR)
- Helmholtz Munich (DE)
- Corresponding author
- Bouras, George
- Edwards, Robert A
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2026-01-05
- Volume
- 54
- Issue
- 1
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC12774648
- OpenAlex
- W7118953414
- Cited by
- 71
- References
- 10
- Citations by year
- 2026: 63 · 2025: 8
- FWCI
- 37.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Australian Government
- National Research Foundation
- Seoul National University
- National Research Foundation of Korea (RS-2021-NR061659, 2020M3‐A9G7‐103933, RS-2024-00396026, RS-2023-00250470, RS-2021-NR056571)
- Novo Nordisk
- Novo Nordisk Fonden (NNF24SA0092560)
- Samsung
- Australian Research Council (FL250100019, DP250103825)
- Topics
- Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- protein structural homology, Foldseek, functional annotation, archaeal viruses, structural alignment, phage therapy
- MeSH terms
- Bacteriophages, Software, Viral Proteins, Genome, Viral, Molecular Sequence Annotation
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