Exploring stereochemical specificity of phosphotriesterase by MM-PBSA and MM-GBSA calculation and steered molecular dynamics simulation.
Wild-type phosphotriesterase (PTE) prefers the SP-enantiomers over the corresponding RP-enantiomers by factors ranging from 10 to 90. To satisfy the binding modes of the PTE of SP- and RP-enantiomers, all-atom molecular dynamics simulations were carried out on two paraoxon SPand RPderivatives, namely, Sp-1 and Rp-1. Molecular mechanics Poisson-Boltzmann surface area and molecular mechanics generalized Born surface area (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 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.
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , School of Life Science, Jilin University , Changchun 130023 , China.
Jingxuan
J
Zhu
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , School of Life Science, Jilin University , Changchun 130023 , China.
Xin
X
Li
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , School of Life Science, Jilin University , Changchun 130023 , China.
Siqi
S
Zhang
a Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , School of Life Science, Jilin University , Changchun 130023 , China.
Hen
H
Ye
b Institute of Tropical Bioscience and Biotechnology , Chinese Academy of Tropical Agricultural Sciences , Changchun 130023 , China.
Hui
H
Zhao
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
D000409:Alanine / Q000737:chemistry; D001665:Binding Sites; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D044345:Phosphoric Triester Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D012372:ROC Curve; D013237:Stereoisomerism
D008024:Ligands; D044345:Phosphoric Triester Hydrolases; D000409:Alanine
MM-PBSA and MM-GBSA calculation; docking; phosphotriesterase; steered molecular dynamics simulation; stereoselectivity