A Hybrid Ensemble End-to-End Neural Network for Accurate Protein-Protein Interactions Prediction

Protein-protein interactions (PPIs) are fundamental to understanding cellular mechanisms, signaling networks, disease pathways, and drug development. Over the years, numerous computational models with artificial intelligence (AI) have been developed to predict PPIs. However, these models mostly face significant challenges, such as fragmented feature extraction pipelines, inability to capture complex global relationships among proteins, and reliance on handcrafted features. These challenges often limit their prediction accuracy. To address these issues, the Knowledge Graph Fused Graph Neural Network (KGF-GNN) was proposed, offering an end-to-end learning approach that integrates Protein Associated Network (PAN) with observed PPI data. While KGF-GNN achieves notable performance improvements, it focuses primarily on local topological features extracted by Graph Neural Networks (GNNs), potentially overlooking critical global patterns. Moreover, its feature fusion process lacks the flexibility to effectively combine diverse biological information. To overcome these shortcomings, this paper introduces a Hybrid Ensemble End-to-End Neural Network (HEENN), which incorporates three key innovations: (1) Local Feature Extraction via Graph Attention Network (GAT): HEENN employs GAT to enable more precise extraction of local topological and semantic features, allowing the model to focus on the most relevant interactions and relationships within the data. (2) Global Feature Extraction via AutoEncoder: By leveraging an AutoEncoder framework, HEENN captures comprehensive global features from PANs and PPI datasets, complementing the GAT's local features to produce richer protein representations. (3) Attention-Enhanced Feature Fusion: An attention mechanism is employed during feature fusion to ensure an adaptive and effective integration of local and global features. Extensive experiments on real-world PPI datasets demonstrate that HEENN significantly outperforms KGF-GNN and other state-of-the-art models, achieving superior accuracy in PPI prediction. These advancements underscore the potential of HEENN in AI-driven bioinformatics research, which offers new opportunities for biological discovery and therapeutic innovation.