title: A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.
abstract: 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 investigate the effects on the dynamics and protein structure when the catalytic Serine 203 is phosphonylated. We find that the soman phosphonylation of the active site Ser203 follows a water assisted addition-elimination mechanism with the elimination of the fluoride ion being the highest energy barrier at 6.5 kcal/mole. We observe soman-dependent changes in backbone and sidechain 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 provide alternative pathways into and out of the hAChE active site. In the soman-adducted protein both side and back door pathways are viable for soman adduct access. Correlation analysis of the apo and soman adducted MD trajectories shows that the correlation of gorge entrance and back door motion is disrupted when hAChE is adducted. This supports the hypothesis that substrate and product can use two different pathways as entry and exit sites in the apo form of the protein. These alternative pathways have important implications for the rational design of medical countermeasures.
authors: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore CA, United States of America.
authors: Brian J
authors: BJ
authors: Bennion
authors: Bioinformatics and Genetics Department, Faculty of Engineering and Natural Sciences, Kadir Has University, 34083 Fatih, Istanbul, Turkey.
authors: Sebnem G
authors: SG
authors: Essiz
authors: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore CA, United States of America.
authors: Edmond Y
authors: EY
authors: Lau
authors: Center for Applied Scientific Computing, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore CA, United States of America.
authors: Jean-Luc
authors: JL
authors: Fattebert
authors: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore CA, United States of America.
authors: Aiyana
authors: A
authors: Emigh
authors: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Ave, Livermore CA, United States of America.
authors: Felice C
authors: FC
authors: Lightstone
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D020134:Catalytic Domain / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation / Q000187:drug effects*; D012999:Soman / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D012999:Soman; D000110:Acetylcholinesterase