BiToxNet: a deep learning framework integrating multimodal features for accurate identification of neurotoxic peptides and proteins

Accurate prediction of the neurotoxicity of peptides and proteins is critically important for the safety assessment of protein therapeutics and the development of protein-based drugs. Although experimental methods can reliably identify neurotoxic peptides and neurotoxins, they are labor-intensive, costly, and unsuitable for large-scale screening. Existing computational approaches are often limited by shallow feature engineering and suboptimal multimodal fusion strategies, which restrict their predictive accuracy and generalizability in real-world applications. In this study, we propose BiToxNet, a deep learning framework that integrates evolutionary embeddings derived from a protein large language model with ten handcrafted biochemical descriptors through a bilinear attention network (BAN). This design enables effective modeling of cross-modal interactions and residue-level dependencies critical for neurotoxicity prediction. BiToxNet was evaluated on three datasets of different sequence lengths, namely Protein, Peptide, and Combined datasets, achieving accuracies of 92.3%, 96.0%, and 92.7%, respectively, and consistently outperforming existing state-of-the-art methods. Ablation studies confirmed the importance of both evolutionary embeddings and handcrafted features, as well as the critical role of BAN in feature fusion. Visualization analyses using t-SNE and hierarchical clustering further demonstrated that BiToxNet learns highly discriminative representations without reliance on domain-specific prior knowledge. Additional evaluation on an external imbalanced dataset validated the robustness and strong generalization capability of the proposed framework. Overall, BiToxNet provides a powerful and generalizable computational framework for the accurate identification of neurotoxic peptides and proteins. By effectively integrating evolutionary and biochemical information through bilinear attention, BiToxNet offers a valuable tool for neurotoxin screening and protein drug safety assessment, and presents a distinctive modeling strategy applicable to a wide range of biological sequence analysis tasks.