Rapid and Sensitive Protein Complex Alignment with Foldseek-Multimer

Kim, Woosub; Mirdita, Milot; Karin, Eli Levy; Gilchrist, Cameron L.M.; Schweke, Hugo; Söding, Johannes; Levy, Emmanuel D.; Steinegger, Martin

doi:10.1101/2024.04.14.589414

Cited by 4 publications

References 32 publications

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BFVD—a large repository of predicted viral protein structures

Kim,

Levy Karin,

Mirdita

et al. 2024

Nucleic Acids Research

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The AlphaFold Protein Structure Database (AFDB) is the largest repository of accurately predicted structures with taxonomic labels. Despite providing predictions for over 214 million UniProt entries, the AFDB does not cover viral sequences, severely limiting their study. To address this, we created the Big Fantastic Virus Database (BFVD), a repository of 351 242 protein structures predicted by applying ColabFold to the viral sequence representatives of the UniRef30 clusters. By utilizing homology searches across two petabases of assembled sequencing data, we improved 36% of these structure predictions beyond ColabFold’s initial results. BFVD holds a unique repertoire of protein structures as over 62% of its entries show no or low structural similarity to existing repositories. We demonstrate how a substantial fraction of bacteriophage proteins, which remained unannotated based on their sequences, can be matched with similar structures from BFVD. In that, BFVD is on par with the AFDB, while holding nearly three orders of magnitude fewer structures. BFVD is an important virus-specific expansion to protein structure repositories, offering new opportunities to advance viral research. BFVD can be freely downloaded at bfvd.steineggerlab.workers.dev and queried using Foldseek and UniProt labels at bfvd.foldseek.com.

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BFVD—a large repository of predicted viral protein structures

Kim,

Levy Karin,

Mirdita

et al. 2024

Nucleic Acids Research

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Multiple Protein Structure Alignment at Scale with FoldMason

Gilchrist,

Mirdita,

Steinegger

2024

Preprint

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Protein structure is conserved beyond sequence, making multiple structural alignment (MSTA) essential for analyzing distantly related proteins. Computational prediction methods have vastly extended our repository of available proteins structures, requiring fast and accurate MSTA methods. Here, we introduce FoldMason, a progressive MSTA method that leverages the structural alphabet from Foldseek, a pairwise structural aligner, for multiple alignment of hundreds of thousands of protein structures. FoldMason computes confidence scores, offers interactive visualizations, and provides essential speed and accuracy for large-scale protein structure analysis in the era of accurate structure prediction. Using Flaviviridae glycoproteins, we demonstrate how FoldMason’s MSTAs support phylogenetic analysis below the twilight zone. FoldMason is free open-source software:foldmason.foldseek.comand webserver:search.foldseek.com/foldmason.Contactgamcil@snu.ac.kr,martin.steinegger@snu.ac.kr

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Gaia: A Context-Aware Sequence Search and Discovery Tool for Microbial Proteins

Jha,

Kravitz,

West-Roberts

et al. 2024

Preprint

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Protein sequence similarity search is fundamental to genomics research, but current methods are typically not able to consider crucial genomic context information that can be indicative of protein function, especially in microbial systems. Here we present Gaia (Genomic AI Annotator), a sequence annotation platform that enables rapid, context-aware protein sequence search across genomic datasets. Gaia leverages gLM2, a mixed-modality genomic language model trained on both amino acid sequences and their genomic neighborhoods to generate embeddings that integrate sequence-structure-context information. This approach allows for the identification of functionally related genes that are found in conserved genomic contexts, which may be missed by traditional sequence- or structure-based search alone. Gaia enables real-time search of a curated database comprising over 85M protein clusters (defined at 90% sequence identity) from 131,744 microbial genomes. We compare the sequence, structure and context sensitivity of gLM2 embedding-based search against existing tools like MMseqs2 and Foldseek. We showcase Gaia-enabled discoveries of phage tail proteins and siderophore synthesis loci that were previously difficult to annotate with traditional tools. Gaia search is freely available at https://gaia.tatta.bio

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Rapid and Sensitive Protein Complex Alignment with Foldseek-Multimer

Cited by 4 publications

References 32 publications

BFVD—a large repository of predicted viral protein structures

BFVD—a large repository of predicted viral protein structures

Multiple Protein Structure Alignment at Scale with FoldMason

Gaia: A Context-Aware Sequence Search and Discovery Tool for Microbial Proteins

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