Phage display-derived peptides as molecular probes for predicting Staphylococcal Exfoliative Toxin-Desmoglein 1 interactions.

Staphylococcal exfoliative toxins (ETs) are serine proteases that cleave desmoglein 1 (Dsg1), a protein critical for epidermal integrity, leading to severe skin conditions. While the specificity of ETs for Dsg1 has been partially studied, the molecular determinants of ET-Dsg1 recognition remain unclear. In this study, we used phage display biopanning and computational modeling to map the interaction between ETs and Dsg1. Peptides selected against two ETs, ETA and ExhC, were aligned with the ectodomain 3 (EC3) sequences of Dsg1, identifying key residues involved in toxin binding. In parallel, molecular dynamics (MD) simulations of ET-peptide systems revealed putative binding sites on the toxins, including a previously uncharacterized allosteric site (site 1), which may contribute to substrate recognition and positioning for catalysis. These results were subsequently employed to model the ET-Dsg1 complex through molecular docking. We predicted that electrostatic complementarity at the protein-protein interface is a key factor underlying ET specificity for Dsg1 isoforms. Our findings provide a structural basis for understanding ET-Dsg1 interactions and offer insights for designing therapeutic inhibitors against ET-related pathologies. The study also highlights the potential of combining phage display and molecular modeling to investigate protein-protein interactions.