Mining the endogenous peptidome for peptide binders with deep learning-driven optimization and molecular simulations

Peptides are short amino-acid chains that mediate essential biological processes, including antimicrobial defence, immune modulation and cell signalling. Their high degree of modularity, biocompatibility and capacity to bind proteins with high specificity make them attractive therapeutic candidates. However, identifying peptides that bind and modulate the function of specific proteins remains challenging due to the immense size of the peptide sequence space. To adress this challenge, we developed BoPep (Bayesian Optimization for Peptides), an end-to-end modular framework that effectively navigates the landscape of peptide-protein interactions by directing the search toward informative regions of sequence space and prioritizes candidates with high binding potential. By focusing computational effort where it is most informative and using calibrated uncertainty to balance exploration and exploitation, BoPep reduces the number of expensive docking evaluations by orders of magnitudes. We demonstrate the utility of BoPep by applying it to three sources of peptides: endogenous proteolytic fragments from clinical wound fluids, the complete human proteome, and a de novo design peptide landscape generated by diffusion-based backbone sampling. Using these sources, we uncover novel encrypted peptide classes that bind CD14 and identify peptides that neutralize the hemolytic activity of pneumolysin, a major bacterial virulence factor. Together, these findings show that BoPep accelerates the identification of testable therapeutic leads from large and diverse peptide collections. BoPep is available at GitHub.