A deep learning framework for comprehensive prediction of human RNA G-quadruplex-binding proteins.

motivationG-quadruplex-binding proteins (G4BPs) play key roles in RNA metabolism and stress response, yet their identification remains experimentally challenging. Here, we present a deep learning (DL) framework for the prediction of RNA G4BPs (RG4BPs), integrating diverse encoding strategies and neural architectures. Our best-performing model, which includes ESM-2 protein language model embeddings and consists of an LSTM architecture, achieved 86% accuracy in distinguishing RG4BPs from non-binder proteins. The application of this model to the human proteome uncovered 2160 high-confidence RG4BP candidates, many of which display intrinsically disordered regions (IDRs) and enrichment in stress granule organelles. These findings reveal a potential link between G-quadruplex recognition and cellular stress responses. To enable easy and broad access to the framework, we developed G4REP, a web server for RG4BP prediction and analysis. Overall, an effective approach to explore the RG4BPs landscape and uncover novel players in RNA regulation is provided. AVAILABILITY: Source code for the G4REP Model training and evaluation is available at: https://github.com/G4REP/G4REPmodel and at https://doi.org/10.5281/zenodo.17963046. G4REP Server is hosted at: https://schubert.bio.uniroma1.it/g4/.