In silico engineering of nuclear-targeted peptides targeting the AP-1 transcriptional complex

Activator protein-1 (AP-1) is a transcription factor implicated in tumor progression but remains difficult to inhibit pharmacologically due to its extended protein–DNA interface. Structure-guided docking of a curated peptide library against the AP-1 complex (PDB: 1FOS) prioritized the soybean-derived decapeptide SKWQHQQDSC as the top-ranked candidate in the docking workflow (GlideScore –9.396 kcal/mol), outperforming the reference peptide under identical conditions. Interaction analysis suggested dual engagement of AP-1 protein residues and DNA bases within the bZIP interface. A 200 ns molecular dynamics simulation of the peptide–protein complex (DNA excluded for focused interfacial analysis) supported structural convergence, preserved α-helical architecture, and persistent electrostatic contacts over the simulated timescale. Nuclear-targeted variants incorporating a classical NLS were evaluated using fully flexible docking. Progressive rigidification via α-helical EAAAK linkers improved structural convergence and minimized nonspecific NLS participation, with the double rigid-linker construct exhibiting the most focused binding mode. Overall, these findings support linker rigidity as an important design parameter in multifunctional peptide engineering targeting transcription factor interfaces.