Molecular dynamics of organophosphorous hydrolases bound to the nerve agent soman

The organophosphorous hydrolase (OPH) from Pseudomonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. Although the natural substrate for OPH is unknown, its triple-mutant H254G/H257W/L303T exhibits a 3 order of magnitude increase in catalytic efficiency and modified stereospecificity toward the most toxic SpSc enantiomer of soman. Molecular dynamics simulations and binding free-energy calculations have been undertaken for the wild-type and triple-mutant H254G/H257W/L303T enzymes bound to the SpSc-soman enantiomer. Comparison of the simulations indicates that substrate binding induces conformational changes of the loops near the active site. The coordination of the zinc cations in the active site of OPH differs between the free enzyme and the complexes. This suggests that the active site of OPH can accommodate several catalytically active coordination geometries, consistent with the fact that the enzymatic activity of the wild-type OPH can be enhanced by alterations to the metal content of the enzyme. It is also argued that the enhanced efficiency of the triple mutant is determined by enzyme-transition-state complementarity. These results provide a qualitative, molecular-level explanation for the 3 order of magnitude increase in catalytic efficiency of the triple-mutant toward SpSc-soman.