BindCORE: Biophysical Ensemble Learning for Predicting Interaction Sites in Intrinsically Disordered Regions

Abstract

Intrinsically disordered proteins and regions (IDPs/IDRs) mediate diverse cellular functions through binding segments whose functional properties are encoded in dynamic conformational ensembles rather than a single static state. Existing predictors of linear interacting peptides (LIPs) and molecular recognition features (MoRFs) rely primarily on sequence-derived features, leaving ensemble-level biophysical properties largely unexplored. Here, we introduce BindCORE, an ensemble-aware deep learning framework that integrates global, local, and pairwise biophysical descriptors to predict interaction sites within IDRs. These features are processed through a multi-scale architecture that enables information exchange between sequence- and ensemble-based global, local, and pairwise information. Across established LIP and MoRF benchmarks, BindCORE consistently improves performance over sequence-based baselines, demonstrating the predictive signals of ensemble-derived properties beyond sequence-based representations alone. Feature-attribution analyses reveal that pairwise descriptors are the dominant contributors to prediction, while solvent accessibility, backbone dihedral entropy, and global geometric properties provide complementary information. Feature-importance rankings vary substantially across ensemble flavours, indicating that different conformational generators encode distinct biophysical signatures of interaction-site propensity. Together, our results show that conformational ensembles contain interpretable determinants of LIP and MoRF binding residues and establish BindCORE as a general framework for incorporating biophysical information into the prediction of functional regions in intrinsically disordered proteins. BindCORE is freely available as a ready-to-use Google Colab notebook (BindCORE Colab notebook). Key Messages BindCORE integrates ensemble-derived biophysical descriptors to predict residue-level interaction sites in intrinsically disordered proteins. Ensemble-derived features improve prediction performance over state-of-the-art sequence-based methods on both LIP and MoRF benchmarks. Pairwise ensemble descriptors, especially contact and dynamic cross-correlation maps, provide the strongest signals for predicting interaction-site residues, while global chain geometry, solvent accessibility, and backbone dihedral preferences add complementary information.