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

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.

Intermolecular Interactions of Nucleoside Antibiotic Tunicamycin with On-Target MraYCB-TUN and Off-Target DPAGT1-TUN in the Active Sites Delineated by Quantum Mechanics/Molecular Mechanics Calculations

“…It is worth noting that the whole H-bonds detected within both active sites by the QTAIM analysis are in accordance with the predicted H-bonds for these two active sites by the experimental findings. ,, In addition to the intermolecular interactions identified in the uracil-binding pocket, the electrostatic interaction of the π···π stacking type occurs between the π electron clouds of the uracil moiety and the aromatic ring of either Phe249 in DPAGT1 or Phe228 in MraY CB . This interaction that plays an important role in stacking the TUN uracil base inside the pertinent active site is also observed between the uracil moiety of muraymycin D2 (MD2) and the aromatic ring of Phe262 in the MraY AA –MD2 complex. , Finally, in agreement with the prediction of our MD simulations, a comparison of the entireties of the | E HB |, E (2) , and | E interaction | amounts related to the TUN–residue/Wt pairs in each binding pocket of DPAGT1–TUN with those in the corresponding biding pocket of MraY CB –TUN indicates that the active site of DPAGT1–TUN is much more stable than that of MraY CB –TUN.…”

“… 30 − 32 Bader’s quantum theory of atoms in molecules (QTAIM) 33 − 35 and natural bond orbital (NBO) analyses 36 , 37 are two reliable theoretical approaches to gain further insights into the nature and strength of the intermolecular interactions, especially the H-bonding interactions, in the protein structures. 24 , 25 , 38 − 40 …”

“…It is clear that noncovalent intermolecular interactions play fundamental roles in the potent inhibitor binding to the active site of its targeted enzyme in order to form a tightly bound enzyme–inhibitor complex. These interactions are classified into three categories comprising electrostatic, van der Waals (vdW), and hydrogen-bonding (H-bonding) interactions. − Deeper insights into the active sites of DPAGT1–TUN and MraY CB –TUN complexes can be gained by determining the nature and strength of intermolecular interactions between TUN and its adjacent residues inside each of these active sites. From a theoretical standpoint, comprehensive description of these interactions requires the use of applicable computational methods.…”

“…From a theoretical standpoint, comprehensive description of these interactions requires the use of applicable computational methods. Nowadays, parallel progress in computational softwares and development in computer architectures, the combined quantum mechanics/molecular mechanics calculations have been deemed as a powerful computational chemistry method to study the protein–ligand interactions. − On the other hand, the M06 family of density functional theory (DFT) comprises suitable functionals to compute noncovalent intermolecular interactions, such as hybrid meta-GGA density functional (M06-2X). − Bader’s quantum theory of atoms in molecules (QTAIM) − and natural bond orbital (NBO) analyses , are two reliable theoretical approaches to gain further insights into the nature and strength of the intermolecular interactions, especially the H-bonding interactions, in the protein structures. ,,− …”

Hydrogen Bonds and n → π* Interactions in the Acetylation of Propranolol Catalyzed by Candida antarctica Lipase B: A QTAIM Study

“…Bader in his theory proposed to distinguish between two kinds of chemical bonds: the shared shell (SS) and the closed shell interactions based on ρ­( r c ) and ∇ 2 ρ­( r c ). The first type of bonds is usually associated with covalent bonds, and examples of the second type are the ionic and the hydrogen bond (HB). , Another QTAIM application is the analysis of molecular interactions between proteins and ligands. − These studies show the importance of HBs on the stabilization of ligands inside a protein active site. Another example of an interaction is the n → π* interaction.…”