The bacterial enzyme phosphotriesterase (PTE) exhibits stereoselectivity toward hydrolysis of chiral substrates with a preference for the Sp enantiomer. In this work, docking analysis and two explicit-solvent molecular dynamics (MD) simulations were performed to characterize and differentiate the structural dynamics of PTE bound to the Sp and Rp paraoxon derivative enantiomers (Rp-1 and Sp-1) hydrolyzed with distinct catalytic efficiencies. Comparative analysis of the molecular trajectories for PTE bound to Rp-1 and Sp-1 suggested that substrate binding induced conformational changes in the loops near the active site. After 100 ns of MD simulation, the Zn β(2+) metal ion formed hexacoordinated- and tetracoordinated geometries in the Sp-1-PTE and Rp-1-PTE ensembles, respectively. Simulation results further showed that the hydrogen bond between Asp301 and His254 occurred with a higher probability after Sp-1 binding to PTE (47.5%) than that after Rp-1 binding (22.2%). These results provide a qualitative and molecular-level explanation for the 10 orders of magnitude increase in the catalytic efficiency of PTE toward the Sp enantiomer of paraoxon.
Keywords: docking; molecular dynamics; paraoxon derivatives enantiomer; phosphotriesterase; stereoselectivity.