LINKER-Pred: A Deep Learning Method and Web-Server for the Prediction of Disordered Flexible Linkers in Proteins

Abstract

Disordered Flexible Linkers (DFLs) are unstructured regions that play critical roles in inter-domain communication and multivalent protein interactions. Despite their biological significance, the accurate identification of DFLs remains challenging due to limited experimental annotations and sparsity of dedicated prediction tools. Here we introduce LINKER-Pred, a publicly available web server featuring two convolutional neural network-based predictors trained on a novel large-scale dataset of linkers connecting folded domains (DLD dataset) and DisProt linkers. LINKER-Pred2 combines ProtTrans and MSA-Transformer embeddings within an ensemble CNN framework, achieving state-of-the-art performance on CAID2 and CAID3 benchmarks. LINKER-Pred-Lite excludes MSA-based features, improving speed while maintaining competitive predictive accuracy. LINKER-Pred predictors offer robust residue-level DFL predictions directly from sequence, providing a scalable solution for DFL annotation across proteomes. The LINKER-Pred web server and associated resources are freely available at https://linkerpred.chemeslab.org/, offering the research community an accessible tool for studying protein disorder and modularity.