PepBAN: A Deep Learning Framework with Bilinear Attention and Adversarial Learning for Peptide-Protein Interaction...

Accurate prediction of the peptide-protein interaction (PepPI) is crucial for developing peptide-based therapeutics and vaccines. However, this computational task has traditionally faced significant challenges, such as the scarcity of structure data along with the corresponding label of the binding affinity for bound complexes. To address these challenges, we introduce PepBAN, a deep learning framework for modeling PepPI predictions. PepBAN incorporates two technical advancements: (1) adopting the protein language model ESM-2 to characterize proteins and ESM-2 or a graph-based foundation model for peptides without structure data and (2) leveraging the conditional domain adversarial learning to enhance generalization across a broad range of protein targets, especially when there are limited binding data. At the core of PepBAN is a bilinear attention network (BAN) that effectively learns the pattern of pairwise local interactions, enables the identification of key residues participating in the peptide-protein interactions, and offers an intuitive approach to interpret the underlying mechanisms of PepPIs via analyzing attention weights. Our numerical experiments demonstrated that PepBAN outperformed the previous state-of-the-art models across several well-established benchmark studies. Furthermore, we evaluated PepBAN's applicability in predicting cyclic peptide-protein interactions, a task that poses significant challenges due to the presence of noncanonical amino acids. These nonstandard residues require specialized handling, which most existing sequence-based PepPI prediction models did not adequately address, and we adopt an atom-resolved molecular graph approach to process cyclic peptides. Despite this complexity, PepBAN demonstrated a clear advantage by achieving a superior prediction performance and offering a distinct edge in tackling the emerging chemical space of cyclic peptides, which has great potential for novel therapeutic development. In summary, PepBAN serves as a valuable tool for advancing peptide-based drug and therapeutic development.