Structure-Guided Design of an Interface-Derived Inhibitor Peptide Against Spodoptera frugiperda Digestive Trypsins.

Abstract

Spodoptera frugiperda is a major agricultural pest whose control requires safer and more sustainable alternatives. In this study, a rational in silico strategy was applied to design a bioinsecticidal peptide targeting digestive trypsin from S. frugiperda, using a functionally relevant interfacial region of the Dioscorin-trypsin complex as a structural template. Interface analysis allowed the identification of an 11-residue oligopeptide designated as PEP-11. Trypsin-peptide docking, pharmacophore profiling, and triplicate molecular dynamics simulations were performed to characterize its interaction with the trypsin model. Docking analysis revealed that PEP-11 binds through a cooperative network of polar and hydrophobic interactions, supporting favorable molecular recognition. Molecular dynamics analyses showed that the trypsin-PEP-11 complex remained stable throughout the 100 ns simulations, with limited structural deviations and flexibility mainly restricted to terminal and loop-exposed regions. In addition, the radius of gyration and solvent-accessible surface area remained stable, while intermolecular hydrogen bonds increased over time. MM/GBSA calculations yielded negative binding free energy values in all replicas, indicating energetically favorable binding. Overall, these results support the computational prioritization of PEP-11 as an interface-derived peptide candidate for future experimental evaluation, including enzymatic inhibition, selectivity, proteolytic stability, and bioactivity assays.