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

Abstract

The bacterial transmembrane enzyme Phospho‐N‐acetylmuramoyl‐pentapeptide translocase from Aquifex aeolicus (MraYAA) 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 MraYAA by inhibiting its function. Since these MraYAA inhibitors have distinct complex chemical structures, the strengths of MraYAA‐inhibitor interactions strongly depend on the inhibitory structure. Here, the crystal structures of MraYAA‐capuramycin, MraYAA‐carbacaprazamycin, and MraYAA‐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 MraYAA active site residues. Our results revealed that Lys70, Thr75, Asp193, Asp196, Gly264, Asp265, and His325 play key roles in binding these inhibitors to MraYAA through hydrogen bonds of common types with strength ranging from van der Waals to covalent characters accompanying electrostatic and van der Waals interactions. MraYAA‐inhibitor interaction energies demonstrated that the MraYAA active site has the strongest intermolecular interactions with capuramycin.