Institute for Protein Design

Computational Protein Design To Improve Detoxification Rates Of Nerve Agents

November 15, 2013    Cherny, I., Greisen P., Ashani Y., et al. (2013).  Engineering V-type nerve agents detoxifying enzymes using computationally focused libraries. ACS chemical biology. 8(11), 2394-403. 

V-type nerve agents are among the most toxic compounds known, and are chemically related to pesticides widespread in the environment. Using an integrated approach, described in an ACS Chemical Biology paper entitled Engineering V-type nerve agents detoxifying enzymes using computationally focused libraries, Dr. Izhack Cherny, Dr. Per Greisen, and collaborators increased the rate of nerve agent detoxification by the enzyme phosphotriesterase (PTE) by 5000-fold by redesigning the active site. Computational models of PTE complexed with V-agents were constructed and Rosetta was used to design multiple rounds of libraries with active site sequence variation to improve substrate interactions and detoxification rates. Five rounds of iteration led to identification of highly active PTE variants that hydrolyze the toxic isomers of V-agents and G-agents; these new enzymes provide the basis for broad spectrum nerve agent detoxification.

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