MFF-HPO: Protein–Phenotype Associations Prediction Based on Sequence Using Multi-Feature Fusion

Protein abnormalities disrupt various cellular and contribute to disease development. Identifying disease-associated proteins is crucial for precision medicine, but traditional methods are time-consuming and costly, necessitating computational approaches. Existing computational methods rely on manual feature engineering and fail to leverage deep features from amino acid sequences and protein structures. In this article, we propose Model for predicting protein-phenotype associations by Fusing multi-view Features (MFF-HPO), a model for predicting protein-phenotype associations by fusing multi-view features from amino acid sequences. First, we generate three-dimensional protein structure from amino acid sequence to derive contact graphs and secondary structures then integrate these with direct sequence encoding and physicochemical properties. Using a Graph Attention Network, we extract structural features from contact graphs, while deep neural networks capture global and local features from secondary structures, physicochemical properties, and sequence encoding. Finally, concatenated features are used to predict phenotype annotations. MFF-HPO outperforms state-of-the-art methods with a mean area under the precision-recall curve of 0.314 and a mean Fmax of 0.371. Ablation studies confirm that multi-view feature fusion enhances predictions, and case studies validate its practicality.