Stereoselectivity of phosphotriesterase with paraoxon derivatives: a computational study.
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.
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Science , Jilin University , Changchun 130023 , China.|b College of Food Science and Engineering , Jilin Agricultural University , Changchun 130118 , China.
Dongling
D
Zhan
c State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , China.
Shanshan
S
Guan
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Science , Jilin University , Changchun 130023 , China.
Hanyong
H
Jin
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Science , Jilin University , Changchun 130023 , China.
Weiwei
W
Han
c State Key Laboratory of Theoretical and Computational Chemistry , Institute of Theoretical Chemistry, Jilin University , Changchun 130023 , China.
Song
S
Wang
D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D007477:Ions / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010261:Paraoxon / Q000737:chemistry*; D044345:Phosphoric Triester Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015032:Zinc / Q000737:chemistry
D002800:Cholinesterase Inhibitors; D007477:Ions; D044345:Phosphoric Triester Hydrolases; D015032:Zinc; D010261:Paraoxon
docking; molecular dynamics; paraoxon derivatives enantiomer; phosphotriesterase; stereoselectivity