The binding mechanism of urea, hydroxamic acid and N-(N-butyl)-phosphoric triamide to the urease active site. A comparative molecular dynamics study

Molecular dynamics (ND) calculations have been performed on the active site of urease from Klebsiella aerogenes and its adducts with urea, hydroxamic acid and N-(n-butyl)-phosphoric triamide (NBPT). The catalytic nickel atoms were explicitly included in all the simulations. The nickel atoms, as shown by X-ray analysis, are linked by a carbamate bridge. Average MD structures were calculated starting from the X-ray structure of the urease active site and docking the ligand and the inhibitors from different starting conformations. The urea molecule binds to only one of the Ni atoms, the hydroxamic acid behaves like a monodentate or a bidentate ligand depending on the pH, and NBPT coordinates both the Ni centers and a carbamate residue via the formation of and hydrogen bond thus acting as a tridentate ligand. The proposed binding mechanisms agree with known data about hydroxamic and urea complexes with urease.