Multistate multiscale docking study of the hydrolysis of toxic nerve agents by phosphotriesterase

The G- and V-type nerve agents are among the most toxic compounds known, where inhalation of a few mg could cause potential death. Over the years wild-type phosphotriesterase (PTE) has gained much attention due to its capability of detoxifying these deadly compounds. The underlying mechanism proceeds via a hydroxyl attack on the P or C centers of the organophosphate nerve agents followed by the departure of the leaving group. Two Zn2+ cations present in the active site center of PTE indirectly assist the hydrolysis. Apart from the wild-type PTE, several designer enzyme variants reportedly catalyze the hydrolysis process much more efficiently. Herein, we studied the hydrolysis of eight toxic compounds with one of the enzyme variants (PTE_27) that show higher efficiency than the wild type as reported in a recent article. We docked both the high energy intermediate state and substrate for all the eight ligands using a consensus docking scheme as implemented in the docking program EnzyDock. Additionally, we investigated the hydrolytic reaction mechanism for all eight ligands employing density functional theory in implicit chloroform solvent and found that hydrolysis for these ligands follows three different possible mechanisms. Finally, EnzyDock successfully predicted correct enantiomeric poses and also score these as low energy docked structures.