Gated-GPS: enhancing protein–protein interaction site prediction with scalable learning and imbalance-aware optimization

In protein-protein interaction site (PPIS) prediction, existing machine learning models struggle with small datasets, limiting their predictive accuracy for unseen proteins. Additionally, class imbalance in protein complexes, where binding residues constitute a small fraction of all residues, hinders model performance. To address these challenges, we constructed a training dataset 9$\times $ larger than previous benchmarks by filtering the latest protein-protein complex data, improving diversity and generalization. We propose Gated-GPS, a Graph Transformer model with a novel gating mechanism designed to effectively leverage this expanded dataset. Additionally, we integrate cross-entropy loss with Tversky Loss to adjust sensitivity to positive and negative samples, mitigating class imbalance by emphasizing underrepresented binding residues. Experimental results show that Gated-GPS outperforms state-of-the-art (SOTA) models across four test sets. Notably, on the UBTest dataset, designed to evaluate generalization on unbounded proteins, our method improves MCC and AUPRC by 18.5% and 21.4%, respectively, over the previous SOTA. In a case study of snake venom toxin-protein interactions, our model accurately identified interaction sites, demonstrating its potential for therapeutic design and advancing the understanding of complex protein interactions.