Metal-Ion Effects on the Polarization of Metal-Bound Water and Infrared Vibrational Modes of the Coordinated Metal Center of Mycobacterium tuberculosis Pyrazinamidase via Quantum Mechanical Calculations

Abstract

Mycobacterium tuberculosis pyrazinamidase (PZAse) is a key enzyme to activate the pro-drug pyrazinamide (PZA). PZAse is a metalloenzyme that coordinates in vitro different divalent metal cofactors in the metal coordination site (MCS). Several metals including Co2+, Mn2+, and Zn2+ are able to reactivate the metal-depleted PZAse in vitro. We use quantum mechanical calculations to investigate the Zn2+, Fe2+, and Mn2+ metal cofactor effects on the local MCS structure, metal–ligand or metal–residue binding energy, and charge distribution. Results suggest that the major metal-dependent changes occur in the metal–ligand binding energy and charge distribution. Zn2+ shows the highest binding energy to the ligands (residues). In addition, Zn2+ and Mn2+ within the PZAse MCS highly polarize the O–H bond of coordinated water molecules in comparison with Fe2+. This suggests that the coordination of Zn2+ or Mn2+ to the PZAse protein facilitates the deprotonation of coordinated water to generate a nucleophile for catalysis as in carboxypeptidase A. Because metal ion binding is relevant to enzymatic reaction, identification of the metal binding event is important. The infrared vibrational mode shift of the C=Nε (His) bond from the M. tuberculosis MCS is the best IR probe to metal complexation.

Pyrazinamide resistance and mutations L19R, R140H, and E144K in Pyrazinamidase of Mycobacterium tuberculosis

“…Catalytic proteins may contain metal ions providing functional properties, such as coordination ability and redox activity. A specific ligand’s combination with the surrounding hydrogen bonding system has a central metal‐like redox potential …”

Analytical hessian fitting schemes for efficient determination of force‐constant parameters in molecular mechanics

“…This is due partly to the growing interest in MM‐ and QM/MM‐type computer simulations of nonbiological molecular systems such as metal–organic frameworks (MOFs), which could sometimes go beyond the chemical space covered by existing parameter sets. In addition, even for biological systems, parameterization is necessary when a metal ion or some other cofactor is involved …”

A computational perspective on the dynamic behaviour of recurrent drug resistance mutations in the pncA gene from Mycobacterium tuberculosis

“…From 200 ns simulations, we revealed that the wild type remained stable, whereas in the mutant form (G97D), the protein destabilized signicantly. AS reported earlier that the Fe 2+ ion inuences the catalysis of this enzyme activity; [45][46][47][48][49] however, mutations can alter these activities. In the current research, novel mutations (F94L, F94S, G97C, G97D, G97S, K96N and K96R) in the pncA gene are shown to have a metal ion effect (Fe 2+ ) on PZase, which is likely to inuence the enzyme activity associated with the conversion of PZA into POA.…”