Multi-Modal Topology-Aware Graph Neural Network for Robust Chemical–Protein Interaction Prediction
Jianshi Wang · International Journal of Molecular Sciences · 2025
Reliable prediction of chemical-protein interactions (CPIs) remains a key challenge in drug discovery, especially under sparse or noisy biological data. We present MM-TCoCPIn, a Multi-Modal Topology-aware Chemical-Protein Interaction Network that integrates three causally grounded modalities-network topology, biomedical semantics, and a 3D protein structure-into an interpretable graph learning framework. The model processes topological features via a CTC (Comprehensive Topological Characteristics)-based encoder, literature-derived semantics via SciBERT (Scientific Bidirectional Encoder Representations from Transformers), and structural geometry via a GVP-GNN (Geometric Vector Perceptron Graph Neural Network) applied to AlphaFold2 contact graphs. Evaluation on datasets from STITCH, STRING, and PubMed shows that MM-TCoCPIn achieves state-of-the-art performance (AUC = 0.93, F1 = 0.92), outperforming uni-modal baselines. Importantly, ablation and counterfactual analyses confirm that each modality contributes distinct biological insight: topology ensures robustness, semantics enhance recall, and structure sharpens precision. This framework offers a scalable and causally interpretable solution for CPI modeling, bridging the gap between predictive accuracy and mechanistic understanding.