MKGR: Multimodal Knowledge-Graph Representation Learning for Cold-Start Protein-Protein Interaction Prediction
Authors: Wenbo Zhang
Organizations: College of Computer and Information Science, Southwest University, Chongqing, Chongqing, China
Abstract
Accurate protein-protein interaction (PPI) prediction is central to functional genomics, disease mechanism discovery, and drug development. A difficult setting arises when candidate interactions include proteins that have no observed PPI edges during training, where models relying on network topology alone often lose useful context. This paper presents \method, a multimodal representation framework for cold-start PPI prediction. \method\ combines region-aware protein sequence encoding with four protein-centered biomedical knowledge graphs, including protein-drug, protein-disease, protein-miRNA, and protein-lncRNA associations. The sequence branch extracts contextual representations from structurally informed sequence regions, while graph attention encoders learn modality-specific protein embeddings from sparse biomedical associations. A bridge reconstruction objective regularizes graph learning by recovering shared protein-entity associations, and a pair-level gating module adaptively integrates sequence and graph evidence for each candidate protein pair. Experiments on two benchmark datasets under novel-old and novel-novel cold-start settings show that \method\ consistently outperforms competitive sequence, network, and knowledge-graph baselines across ACC, F1, AUC, AUPR, and MCC.
Protein-protein interactions (PPIs) are essential for many biological processes. However, existing PPI prediction approaches suffer from two major limitations: they overlook the hierarchical organization of proteins, particularly meso-scale motifs that critically regulate PPIs, and fail to effectively integrate sequence, structure, and function modalities. To address these limitations, we propose MMM-PPI, a Hierarchical Motif-based Multi-Modal protein Encoder for PPI Prediction that constructs PPI embeddings in a bottom-up multi-modal manner across three scales. At the micro-scale, we encode three modal residue features; at the meso-scale, a novel multimodal motif encoder aggregates residues into spatially-informed motif embeddings; at the macro-scale, a multimodal protein encoder integrates motifs into protein embeddings by jointly modeling motif importance and inter-modal correlations. The pre-trained encoder can be used off-the-shelf for large-scale PPI prediction. Extensive experiments on multiple PPI datasets show that MMM-PPI outperforms state-of-the-art multi-label PPI prediction models, particularly under challenging data partitions and limited data scenarios. Codes are in https://github.com/yzf-code/MMM-PPI.
Protein-protein interactions (PPIs) are fundamental to cellular function and disease mechanisms. Current learning-based PPI predictors focus on learning powerful protein representations but neglect designing specialized classification heads. They mainly rely on generic aggregating methods like concatenation or dot products, which lack biological insight. Motivated by the biological "L3 rule", where multiple length-3 paths between a pair of proteins indicate their interaction likelihood, our study addresses this gap by designing a biologically informed PPI classifier. In this paper, we provide empirical evidence that popular PPI datasets strongly support the L3 rule. We propose an L3-path-regularized graph prompt learning method called L3-PPI, which can generate a prompt graph with virtual L3 paths based on protein representations and controls the number of paths. L3-PPI reformulates the classification of protein embedding pairs into a graph-level classification task over the generated prompt graph. This lightweight module seamlessly integrates with PPI predictors as a plug-and-play component, injecting the interaction prior of complementarity to enhance performance. Extensive experiments show that L3-PPI achieves superior performance enhancements over advanced competitors.
RNA-Protein Interactions (RPIs) are critical for regulating cellular functions. While traditional wet-lab experiments for RPI detection are costly and time-consuming, Deep Learning (DL) methods provide an efficient computational alternative for RPI Prediction (RPIP). In particular, Graph Neural Networks (GNNs) are promising, as they naturally model RPI networks. However, existing GNN-based methods often rely on homogeneous graphs or predefined meta-paths, which limit their ability to handle data sparsity and to generalize to cold-start scenarios involving unknown molecules. To address these limitations, we propose Edge Generation-guided Relation-aware Learning (EGRL), a novel framework with several key components: implicit meta-path learning to capture relational semantics without handcrafted paths; a multi-relation-aware attention mechanism for adaptive fusion of interaction patterns; a graph generator that predicts potential ("soft") edges to support cold-start nodes; and a multi-feature fusion predictor for final interaction scoring. EGRL is jointly trained with a primary task loss and an auxiliary generator loss. Comprehensive evaluations on four benchmark datasets demonstrate that EGRL achieves competitive overall performance. More importantly, it exhibits superior generalization in cold-start settings, achieving an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.867 and an Area Under the Precision-Recall curve (AUPR) of 0.861 on unknown molecules, corresponding to improvements of 8.6% in AUROC and 5.0% in AUPR over prior state-of-the-art methods. The code will be released soon.