Theoretical Study of Intermolecular Interactions between Critical Residues of Membrane Protein MraYAA and Promising Antibiotic Muraymycin D2

Saeid Malek Zadeh; Elahe K Astani; Zhe-Chong Wang; Kamal Adhikari; Rajesh Rattinam; Tsung-Lin Li

doi:10.1021/acsomega.0c01551

Theoretical Study of Intermolecular Interactions between Critical Residues of Membrane Protein MraY_AA and Promising Antibiotic Muraymycin D2

ACS Omega. 2020 Sep 2;5(36):22739-22749. doi: 10.1021/acsomega.0c01551. eCollection 2020 Sep 15.

Authors

Saeid Malek Zadeh^{1

2

3}, Elahe K Astani⁴, Zhe-Chong Wang¹, Kamal Adhikari^{1

5

6}, Rajesh Rattinam^{1

2

3}, Tsung-Lin Li^{1

2

5

6}

Affiliations

¹ Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
² Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan.
³ Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
⁴ Department of Chemistry, Faculty of Science, Tarbiat Modares University, Tehran 14115-175, Iran.
⁵ Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan.
⁶ Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan.

Abstract

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.