DLFea4AMPGen de novo design of antimicrobial peptides by integrating features learned from deep learning models

Deep learning models show promise in accelerating the design and optimization of antimicrobial peptides (AMPs), but current methods face challenges, such as low success rates, or large virtual library scales. In this study, we introduce DLFea4AMPGen, a bioactive peptide design strategy that leverages deep learning models to identify and extract key features associated with antimicrobial peptide activity. This approach enables the generation of peptide sequences with potential bioactivities. Using the SHapley Additive exPlanations (SHAP) method, we quantify the contribution of each amino acid in multifunctional peptides with potential antibacterial, antifungal, and antioxidant activities. Key feature fragments (KFFs) with the highest average contributions are extracted and classified into four subfamilies based on amino acid frequency. These high-frequency amino acids are systematically arranged to generate a plausible sequence subspace for candidate peptides, from which 16 representative sequences were selected for experimental validation. The results show that 75% (12/16) of the sequences exhibited at least two types of activity. Notably, D1 exhibits broad-spectrum antimicrobial activity, including efficacy against multidrug-resistant clinical pathogenic isolates both in vitro and in vivo. This proof-of-concept study underscores the potential of the DLFea4AMPGen platform for efficient design and screening of bioactive peptides, showcasing its value in AMP research.