DFT QM/MM MD Calculations to Identify Intermolecular Interactions within the Active Sites of MraYAA Bound to Antibiotics Capuramycin, Carbacaprazamycin, and 3′-Hydroxymureidomycin A

The bacterial transmembrane enzyme Phospho-N-acetylmuramoyl-pentapeptide translocase from Aquifex aeolicus (MraY(AA)) plays an important role in the peptidoglycan biosynthesis of bacterial cell wall. The natural-product nucleoside inhibitors such as capuramycin, carbacaprazamycin, and 3 '-hydroxymureidomycin A block the biosynthetic pathway of MraY(AA) by inhibiting its function. Since these MraY(AA) inhibitors have distinct complex chemical structures, the strengths of MraY(AA)-inhibitor interactions strongly depend on the inhibitory structure. Here, the crystal structures of MraY(AA)-capuramycin, MraY(AA)-carbacaprazamycin, and MraY(AA)-3 '-hydroxymureidomycin A were separately optimized by quantum mechanics/molecular mechanics (QM/MM) approach in conjunction with molecular dynamics (MD) simulations. Further, quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses at the M06-2X/6-31G** level were done on the active site of each optimized structure to specify the characteristics of intermolecular interactions of each cited inhibitor with the MraY(AA) active site residues. Our results revealed that Lys70, Thr75, Asp193, Asp196, Gly264, Asp265, and His325 play key roles in binding these inhibitors to MraY(AA) through hydrogen bonds of common types with strength ranging from van der Waals to covalent characters accompanying electrostatic and van der Waals interactions. MraY(AA)-inhibitor interaction energies demonstrated that the MraY(AA) active site has the strongest intermolecular interactions with capuramycin.

Automated summary

This study investigates the characteristics of interactions between the MraY(AA) enzyme and different inhibitors. The results reveal the crucial roles of Lys70, Thr75, Asp193, Asp196, Gly264, Asp265, and His325 in mediating the interactions between MraY(AA) and inhibitors through hydrogen bonds.