Disruption of Hsp70.14–BAG2 Protein–Protein interactions using deep Learning–Driven peptide design and molecular simulations

Protein-protein interactions (PPIS) are critical in proteostasis, stress response, and disease progression. Targeting the interaction between Hsp70.14 and BAG2, a co-chaperone implicated in oncogenic survival, offers a promising therapeutic approach. This study employed a comprehensive in silico framework to identify bioactive antimicrobial peptides (AMPS) capable of disrupting the Hsp70.14-BAG2 interaction. In this study, we present an integrated in silico pipeline combining deep learning-based peptide screening, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA free energy analysis to identify antimicrobial peptides (AMPS) capable of disrupting the Hsp70.14-BAG2 interaction. Peptides were shortlisted from an extensive public database using stringent physicochemical and safety filters, yielding candidates with high therapeutic potential. DBAASPS_19370 and DBAASPS_17167 exhibited more favourable binding free energies and lower dissociation constants than the reference Hsp70.14-BAG2 complex. Molecular dynamics simulations revealed that one lead peptide demonstrated superior complex stability, characterised by compact structure, reduced flexibility, and solvent exposure. MM/GBSA calculations further validated these observations, revealing the most favourable free energy profile for DBAASPS_19370 compared to the other complexes. Interface analysis showed improved atomic packing, enhanced residue participation, and better solvation energetics in the selected peptide complexes. These findings highlight DBAASPS_19370 as a potent AMP candidate capable of competitively inhibiting BAG2 and disrupting its interaction with Hsp70.14, offering a rational avenue for chaperone-targeted therapeutic development. Future work may explore in vitro validation and structural optimization of this peptide to support its translational potential.