Extending protein language models to a viral genomic scale using biologically induced sparse attention

BACKGROUND: The transformer architecture in deep learning has revolutionized protein sequence analysis. Recent advancements in protein language models have paved the way for significant progress across various domains, including protein function and structure prediction, multiple sequence alignments, and mutation effect prediction. A protein language model is commonly trained on individual proteins, ignoring the interdependencies between sequences within a genome. However, biological understanding reveals that protein-protein interactions span entire genomic regions, underscoring the limitations of focusing solely on individual proteins. FINDINGS: To address these limitations, we propose a novel approach that extends the context size of transformer models across the entire viral genome. By training on large genomic fragments, our method captures putative long-range dependencies consistent with inter-protein relationships and encodes protein sequences with integrated information from distant proteins within the same genome, offering benefits across downstream tasks. Viruses, with their densely packed genomes, minimal intergenic regions, and protein annotation challenges, are ideal candidates for genome-wide learning. We introduce a long-context protein language model, trained on entire viral genomes, leveraging a biologically informed sparse attention mechanism in which inter-protein links are inferred computationally and used as sparsity priors. Our semi-supervised approach supports long sequences of up to 61,000 amino acids (aa). CONCLUSION: Our evaluations show improved prediction of masked aa and improved downstream discrimination relative to single-protein models and long-context baselines, with additional validation that our inferred links correlate with independently curated interaction resources.