Exploring stereochemical specificity of phosphotriesterase by MM-PBSA and MM-GBSA calculation and steered molecular dynamics simulation.

Wild-type phosphotriesterase (PTE) prefers the S-enantiomers over the corresponding R-enantiomers by factors ranging from 10 to 90. To satisfy the binding modes of the PTE of S- and R-enantiomers, all-atom molecular dynamics simulations were carried out on two paraoxon S and R derivatives, namely, S-1 and R-1. Molecular mechanics Poisson-Boltzmann surface area and molecular mechanics generalized Born surface area (MM-PBSA and MM-GBSA) calculations indicated that His230 in S-1-PTE had a closer interaction with the substrate than that in R-1-PTE and that such interaction increased the catalytic efficiency of PTE for S-1. The steered molecular dynamics simulation indicated that, compared with S-1, R-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 S-1 unbinding pathway via PTE, whereas Tyr309 alone is considered an important residue for the R-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.