SLiMNet: a deep learning model to detect short linear motifs using protein large language model representations and paired inputs

Abstract Short linear motifs (SLiMs) are short (3-15 amino acids in length) segments within intrinsically disordered regions (IDRs) that mediate transient protein–protein interactions as well as other functions such as stability and subcellular localization. Only a few thousand out of likely hundreds of thousands have been experimentally validated. SLiMs can be detected as conserved regions inside of IDRs using local alignments, though current approaches have limited sensitivity and specificity and are unable to functionally annotate their hits. Assigning function is hence a major outstanding issue in SLiM biology. Here we present SLiMNet, a deep learning model inspired by siamese networks and contrastive learning that predicts functional similarity in pairs of SLiMs. SLiMNet uses uses protein large language model embeddings and is trained on annotated sets of SLiMs. We show that it detects shared function in unseen, non-redundant motif pairs, and its scores correlate with experimental binding strengths from deep mutational scanning of cyclin-binding motifs. Using SLiMNet we provide repositories of putative SLiM pairs derived from annotated IDR regions for to help with hypothesis generation for the functional annotation of SLiMs. This includes an atlas generated from all-by-all scoring 16-mers from tiled IDRs from the DisProt database. We show that it captures a new nuclear localization motif recently added to MoMaP and a PRMT1 methylation motif in the literature. We also provided a repository of all IDRs scored with SLiMNet against against all MoMaP instances, and an atlas of potential functional pairs for 256 known orphan motifs (motifs with only a single known instance with essential function). Collectively, these atlases are useful resources for the SLiM biology community. Competing Interest Statement P.M.K. is a co-founder and consultant to several biotechnology companies, including Fable Therapeutics, Resolute Bio, and Navega Therapeutics. P.M.K. also serves on the scientific advisory board of ProteinQure. M.C.M. has been a consultant at Rime Therapeutics and Fable Therapeutics. Footnotes The InfoNCE loss was repeatedly, incorrectly called the InfoCNE loss.