Linear-time prediction of proteome-scale microbial protein interactions

Abstract Protein-protein interactions (PPIs) underpin biological function, yet proteome-scale interaction prediction remains bottlenecked by the quadratic computational complexity of all-vs-all pairwise comparisons. Here, we present FlashPPI, a contrastive learning framework, grounded in residue-level interactions, that enables linear-time prediction of physical protein interfaces across a microbial proteome. By leveraging a genomic language model that captures cross-protein co-evolutionary signals from metagenomic sequences, FlashPPI aligns interacting partners in a shared latent space. We demonstrate a four-fold performance increase over existing sequence-based methods, while reducing proteome-wide screening time from days to minutes. Crucially, FlashPPI achieves comparable screening performance to state-of-the-art structure-folding models at a fraction of the computational cost. Finally, we integrate FlashPPI into seqhub.org, an interactive web platform that combines predicted networks with functional annotations and genomic context, making proteome-wide network analysis rapid and accessible for microbial discovery. Competing Interest Statement The authors have declared no competing interest.