Recent efforts in structural phylogenetics have highlighted their ability to resolve deeper evolutionary relationships than traditional sequence-based methods. These approaches hold promise for elucidating phylogenetic and taxonomic relationships within the virosphere which tend to escape traditional phylogenetics due to the pace of viral evolution. However, the paucity of available structures for the incredible observable diversity of extant viruses and the computational cost of inferring structures has prevented a systematic structural exploration of the virosphere. We have fine-tuned ESMc to produce structural tokens through Foldseek's 3Di alphabet using the structures available in the AlphaFold2-based structures available in the Big Fantastic Virus Database. We have succeeded in producing a viral-focused protein LLM which allows for rapid conversion of amino acid sequences into 3Di tokens and opens up the voluminous viral sequencing datasets for structurally informed homology searching and phylogenetics through the use of Foldseek. We have also created a pipelines and tools for infering cleavage sites, constructing phylogenies of structurally homologous cleaved products, annotation of functional content and the construction of 'taxonomic' consensus trees centered around the structure enhanced representation of viral proteomes.

Co-authors: Christophe Dessimoz, Dongwook Kim