Learning motif features and topological structure of molecules for metabolic pathway prediction

Metabolites serve as crucial biomarkers for assessing disease progression and understanding underlying pathogenic mechanisms. However, when the metabolic pathway category of metabolites is unknown, researchers face challenges in conducting metabolomic analyses. Due to the complexity of wet laboratory experimentation for pathway identification, there is a growing demand for predictive methods. Various computational approaches, including machine learning and graph neural networks, have been proposed; however, interpretability remains a challenge. We have developed a neural network framework called MotifMol3D, which is designed for predicting molecular metabolic pathway categories. This framework introduces motif information to mine local features of small-sample molecules, combining with graph neural network and 3D information to complete the prediction task. Using a dataset of 5,698 molecules that participate in 11 metabolic pathway categories in the KEGG database, MotifMol3D outperformed state-of-the-art methods in precision, recall, and F1 score. In addition, ablation study and motif analysis have demonstrated the effectiveness and usefulness of the model. Motif analysis, in particular, has shown motif information can actually characterize the main features of specific pathway molecules to a certain extent and enhance the interpretability of the model. An external validation further corroborates this observation. MotifMol3D is an open-source tool that is available at https://github.com/Irena-Zhang/MotifMol3D.git. Scientific contribution MotifMol3D integrates motif information, graph neural networks, and 3D structural data to enhance feature extraction for small-sample molecules, improving the precision and interpretability of metabolic pathway predictions. The model outperforms state-of-the-art approaches in precision, recall, and F1 score. This work reveals how motif information characterizes pathway-specific molecules, offering novel insights into molecular properties within metabolic pathways.