Genome-scale metabolic models (GEMs) can effectively facilitate many fields in synthetic biology, biomanufacturing, and biomedicine. Reconstructing high-quality GEMs is crucial for accurate phenotype predictions of organisms. However, draft GEMs generated by automated reconstruction tools contain many knowledge gaps, especially missing reactions. The existing machine learning-based gap-filling approaches need to be further developed. In this article, we propose a novel HyperGraph Learning approach with Multi-dimensional metabolite feature extractions and static-dynamic Attention mechanisms (HGLMA) for predicting and teasing out missing reactions in GEM gap-fillings. HGLMA simultaneously uses two pretrained language models to proceed multi-dimensional metabolite feature extractions, which are further fused and regarded as node embeddings for graph learning. The directed and high-order associations between metabolites in reactions of GEMs are deeply mined by successively employing a directional graph network and a hypergraph neural network. Before outputting the predicted confidence score for candidate reactions, the static-dynamic multi-head attention mechanism is utilized to automatically learn attention weights and to identify key metabolites within any candidate reaction. The five-fold cross-validation results on 108 BiGG GEMs show that HGLMA significantly outperforms other state-of-the-art machine learning-based approaches both in prediction performances and in the ability of discovering missing reactions from metabolic reaction pools. The ablation study shows the contributions of multi-dimensional feature extractions and static-dynamic attention mechanisms. In addition, the phenotype prediction results of 24 bacterial organisms demonstrate the effectiveness and superiority of gap-fillings by HGLMA.
Keywords: gap-filling; genome-scale metabolic model; hypergraph learning; pretrained language model; static–dynamic attention mechanism.
© The Author(s) 2026. Published by Oxford University Press.