Irreversible inactivation of human acetylcholinesterase (hAChE) by organophosphorous pesticides (OPs) and chemical weapon agents (CWA) has severe morbidity and mortality consequences. We present data from quantum mechanics/molecular mechanics (QM/MM) and 80 classical molecular dynamics (MD) simulations of the apo and soman-adducted forms of hAChE to understand the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We observe soman-specific changes in backbone and side-chain motions compared to the apo form of the protein. These alterations restrict the soman-adducted hAChE to a structural state that is primed for the soman adduct to be cleaved and removed from the active site. The altered motions and resulting structures have important implications for the rational design of medical countermeasures.This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.  LLNL-644163

Soman as a wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations

248th National Meeting (2014)

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