Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa.

UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is one of the key enzymes involved in peptidoglycan biosynthesis. The peptide HESFWYLPHQSY (called PEP 1354) is an inhibitor of MurA with an IC50 value of 200 μm. In this article, we have used the FlexPepDock ab-initio protocol from the Rosetta program homology modeling and molecular dynamics simulations to analyze, for the first time, the interaction of the PEP 1354 peptide with MurA enzyme from Pseudomonas aeruginosa (MurA-PA). Our modeling results suggest that the peptide binds to the same active site as the natural substrate UDP-N-acetylglucosamine (UNAG). Additionally, the MurA-peptide complex revealed that the peptide seems to prevent the closure of the Pro114-123 loop and, consequently, the open-closed transition of the MurA structure.