Probing the interaction of l-captopril with metallo-β-lactamase CcrA by fluorescence spectra and molecular dynamic simulation

Both the molecular recognition and interaction of metallo-β-lactamase CcrA with l -captopril were studied by the combined use of fluorescence spectra and molecular dynamic simulation. The results showed that the binding constant was 8.89 × 10 4 L mol −1 at 296 K. Both Zn1 and Zn2 displayed tetrahedral coordination geometries in the CcrA–Lcap complex, the S atom in l -captopril displaced the nucleophilic hydroxide in apo CcrA and occupied the fourth coordination site for each ion, resulting in a competitively inhibited CcrA enzyme. Strong electrostatic interaction between the two zinc ions in CcrA and negatively charged l -captopril provided the main driving force for the binding affinity. Through a partly structural transformation from β-sheet to random coil, loop 1 (residues 24–34) completely opened the binding pocket of CcrA to allow an induced fit of the newly introduced ligand. This study may provide some valuable information for designing and developing a more tightly binding inhibitor to resist superbugs.