Theoretical Study of Intermolecular Interactions between Critical Residues of Membrane Protein MraY(AA) and Promising Antibiotic Muraymycin D2

[Image: see text] Phospho-N-acetylmuramoyl-pentapeptide translocase (MraY(AA)) from Aquifex aeolicus is the binding target for the nucleotide antibiotic muraymycin D2 (MD2). MraY(AA) in the presence of the MD2 ligand has been crystallized and released, while the interactions between the ligand and active-site residues remain less quantitatively and qualitatively defined. We characterized theoretically the key residues involved in noncovalent interactions with MD2 in the MraY(AA) active site. We applied the quantum theory of atoms in molecules and natural bond orbital analyses based on the density functional theory method on the solved crystal structure of MraY with the MD2 to quantitatively estimate the intermolecular interactions. The obtained results revealed the presence of multiple hydrogen bonds in the investigated active site with strength ranging from van der Waals to covalent limits. Lys70, Asp193, Gly194, Asp196, Gly264, Ala321, Gln305, and His325 are key active-site residues interacting with MD2. Conventional and unconventional hydrogen bonds in addition with charge–dipole and dipole–dipole interactions contribute significantly to stabilize the MD2 binding to the MraY(AA) active site. It was also found that water molecules inside the active site have substantial effects on its structure stability through hydrogen-bonding interactions with MD2 and the interacting residues.