An Integrated Computational and Biophysical Approach for Investigating the Structure-Function Impact of blaOXA-58...

Carbapenems are the last-resort antibiotic option against A. baumannii infections, and Carbapenem resistance leads to the emergence of CRAB strains, which are difficult to treat. The CRAB novel reported mutation in the blaOXA-58, whose resistance mechanism was not explored. Here, we conducted molecular docking and molecular dynamics simulation to unveil and compare the molecular mechanisms of blaOXA-58 wild and mutant types (I87M, A88L, and double-mutated). The crystal structure of blaOXA-58 was retrieved from PDB, mutations were induced using the AlphaFold online server, and the structures of Carbapenem drugs (DOR, ETP, MEM, and IPM) were retrieved from PubChem database. Using PyRx 0.8, molecular docking was performed between Carbapenem drugs and protein blaOXA-58, both in wild-type and mutant variants. The results were validated through molecular dynamics simulations lasting 100 ns. Docking results showed the binding score of Carbapenem drugs with wild-type blaOXA-58 protein, I87M, A88L, and double-mutated forms, which revealed that the single mutation enhanced the binding affinity of Carbapenems toward the protein. Meanwhile, the decreased binding affinity of Carbapenem toward the double-mutated protein may be due to combined effect of the mutations on the protein structure. Overall, Ertapenem showed good binding scores (-8.1, -8.8, -8.8, and -6.1 kcal/mol), and Imipenem showed weak affinity (-6.3, -5.6, -6.3, and -5 kcal/mol) toward wild-type protein, I87M, A88L, and the double-mutated blaOXA-58 protein, respectively. Wild and double-mutated complexes were subjected to molecular dynamics simulation which revealed mutant-ETP was the most stable complex with low RMSD, RMSF, RoG, and B-factor values. PCA showed reduced flexibility, mutation affected surface loop arrangements in mutant complexes, raising SASA in DOR/IPM, reducing it in ETP, minimal effect in MEM. In contrast, mutant-IPM had higher RMSD, RMSF, RoG, lower hydrogen bonding, and better flexibility. Mutant-DOR exhibited a loss of α-helices and β-strands. The outcomes of the current analysis demonstrated that slight mutation in blaOXA-58 affects working of carbapenem antibiotic. The complicated impact of the double mutation on stability and binding should improve antibiotic-resistant pathogen research by enhancing targeted medication or inhibitor design.