Exploring the molecular recognition between FpvA and colicin E9 immunity protein for disrupting FpvA-mediated Iron uptake in Pseudomonas aeruginosa: an advanced computational study

Confronted with the challenge of antibiotic resistance in the opportunistic pathogen Pseudomonas aeruginosa ( P. aeruginosa ), this study explores a novel anti-virulence strategy targeting the bacterium's critical iron-acquisition machinery. This study hypothesizes that a protein ligand based on the Colicin E9 immunity protein (Im9) scaffold can specifically target the extracellular face of P. aeruginosa 's ferripyoverdine receptor A (FpvA), blocking pyoverdine uptake or inhibiting its transport, thereby disrupting receptor function. Plausible binding could hinder ferripyoverdine binding or lock the receptor, preventing the TonB-dependent conformational changes needed for iron translocation. A comprehensive workflow encompassing docking, molecular dynamics (MD) simulation, and binding energy assessment was implemented to elucidate the interaction mechanism. The docking results showed differences in binding stability and orientation and were further evaluated through 500 ns MD simulations, which illustrated the dynamic behavior of the complexes. The best blind and directed molecular docking approaches were found to show strong affinity, with GOAP scores of −94,908.37 and −95,060.13, respectively. Moreover, the binding affinities calculated by the MMGBSA method from PRODIGY and MD simulations were −12.80 and −14.54 kcal/mol for best blind docking, and −14.60 and −9.27 kcal/mol for best directed docking, respectively. A higher binding affinity on the negative scale strongly suggests a significant association in both static and dynamic states. Hence, this study enhances the understanding of bacterial iron uptake, aids antimicrobial strategy development, provides an atomic model of the FpvA-Im9 complex, identifies key binding factors, and evaluates its stability, serving as a blueprint for designing new therapeutics against P. aeruginosa . • FpvA-Im9 interaction is key to bacterial iron uptake and antimicrobial targets. • Molecular docking, MD simulations, and binding affinity prediction were used. • Molecular docking with LZerD suggested a strong FpvA-Im9 association. • MD simulations revealed the dynamic stability of the FpvA-Im9 complexes. • MMGBSA binding energy indicates a strong affinity of Im9 to FpvA.