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 SP and RP derivatives, 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.

Cellulose triacetate dialyzer reduces platelet loss during continuous veno-venous hemofiltration.

Thrombocytopenia is a common complication in patients receiving continuous veno-venous hemofiltration (CVVH) in the intensive care unit. The hemofilter itself plays an important role in the genesis of thrombocytopenia. The present study was undertaken to test whether there were differences in platelet loss and activation during CVVH with a polysulfone (PS) hemofilter or a cellulose triacetate (CTA) dialyzer. 96 patients with thrombocytopenia and acute kidney injury requiring CVVH were randomly assigned to four groups receiving low-molecular-weight heparin (LMWH) PS (n = 24), LMWH CTA (n = 24), no anticoagulation PS (n = 24), and no anticoagulation CTA (n = 24), respectively. We found a significant decrease in platelet counts, but an increased platelet activation with the PS hemofilter in patients who received no anticoagulation. There was no significant decrease in platelet counts and activation in the CTA group. The cellulose membranes could be an effective alternative to the standard synthetic membranes in patients at high risk for thrombocytopenia during CVVH.