Genomic profiling and molecular dynamics analysis of parDE^Pa toxin-antitoxin homologs targeting DNA gyrase in Pseudomonas aeruginosa: insights from computational investigations

In the realm of hospital-acquired and chronic infections, Pseudomonas aeruginosa stands out, demonstrating significant associations with increased morbidity, mortality, and antibiotic resistance. Antibiotic-resistant strains are believed to contribute to thousands of deaths each year. Chronic and latent infections are associated with the bacterial toxin-antitoxin (TA) system, although the mechanisms involved are poorly understood. This study focuses on a novel type II TA system, parDE^Pa, identified in the genome of P. aeruginosa ATCC 27853. We explored its structural features, functional relationships, and genetic configurations. Our research identified parDE^Pa homologs in P. aeruginosa, clarified their interactions, and highlighted connections to essential cellular metabolic processes. Notably, homologs of the ParD^Pa antitoxin were found to be more conserved than the ParE^Pa toxin. Structural models of the ParE^Pa toxin and ParD^Pa antitoxin confirmed their integrity. Through docking and molecular dynamics simulations, we showed that the ParE^Pa toxin binds to DNA gyrase, inhibiting replication. The stability of the ParD^Pa-ParE^Pa complex is primarily driven by hydrophobic interactions (−1763.2 kcal/mol), while the ParE^Pa-GyrA^Pa interaction is sustained by strong electrostatic forces (−1294.9 kcal/mol). The RMSD scores indicated greater stability for the ParD^Pa-ParE^Pa complex (1.11 Å) than the ParE^Pa-GyrA^Pa complex (1.16 Å). RMSF analysis identified key residues involved in the ParD^Pa-ParE^Pa complex (Leu⁵⁹, Gly⁶⁰, Arg¹¹⁵, Asn¹¹⁶, Arg¹¹⁷) and the ParE^Pa-GyrA^Pa complex (Pro⁴⁸, Gln⁴⁹, Ser⁵⁵, Asp⁹⁴, Gln⁹⁵). These findings significantly enhance our understanding of the structural and metabolic roles of the chromosomally encoded parDE^Pa TA module in P. aeruginosa. © 2024 Informa UK Limited, trading as Taylor & Francis Group.