Exploration Of The Stereoselectivity Of Phosphotriesterase With Paraoxon Derivatives By Several Molecular Dynamics Simulations

Organic phosphorus compounds are used as insecticides and chemical warfare agents for several decades,because of its neurotoxicity,the accumulation of Organic phosphorus compounds in the environment for long-term would bring serious potential threat to human life and production.In order to construct a new type of PTE which can widely catalyze the hydrolysis of this kind of compounds,we adopt a more efficiently and intuitively computer aided simulation program to study the hydrolysis process of Paraoxon derivatives catalyzed by PTE.Wild-type PTE exhibits stereoselectivity toward hydrolysis of chiral substrates with a preference for the Sp enantiomer,Therefore,it is unable to hydrolyze substrates effectively and widely.To satisfy the binding modes of the PTE of Sp and Rp enantiomers,all-atom molecular dynamics simulations were carried out on two paraoxon Sp and Rp derivatives,namely,Sp-1 and Rp-1.Docking analysis reveal that PTE bound to the Sp and Rp paraoxon derivative enantiomers(Rp-1 and Sp-1)hydrolyzed with distinct catalytic efficiencies.Molecular dynamics(MD)simulations suggested that substrate binding induced conformational changes in the loops near the active site.After 100 ns of MD simulation,the β-Zn2+ metal ion formed hexa-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%).MM-PBSA and MM-GBSA calculations indicated that His230 in Sp-1-PTE had a closer interaction with the substrate than that in Rp-1-PTE and that such interaction increased the catalytic efficiency of PTE for Sp-1.The steered molecular dynamics simulation indicated that,compared with Sp-1,Rp-1 in the unbinding(binding)may hinder some residue displacement,thus requiring more effort to escape the binding pocket of PTE.In addition,Trp131,Phe306,and Tyr309 are deemed important residues for the Sp-1 unbinding pathway via PTE,whereas Tyr309 alone is considered an important residue for the Rp-1 unbinding pathway.These results provide a qualitative and molecular-level explanation for the magnitude increase in the catalytic efficiency of PTE toward the Sp enantiomer of paraoxon.Moreover,These results demonstrate the possibility of dramatically altering the stereoselectivity and overall reactivity of the native enzyme toward chiral substrates by modifying specific residues located within the active site of PTE.Our study will provide a reliable theoretical clue for the construction of a new type of PTE with more widely and efficiently catalysis on Organic phosphorus compounds.