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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 hypothesismore » 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.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. Kadir Has Univ., Istanbul (Turkey)
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1399705
Alternate Identifier(s):
OSTI ID: 1200900
Report Number(s):
LLNL-JRNL-644163
Journal ID: ISSN 1932-6203
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 10; Journal Issue: 4; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 45 MILITARY TECHNOLOGY, WEAPONRY, AND NATIONAL DEFENSE

Citation Formats

Bennion, Brian J., Essiz, Sebnem G., Lau, Edmond Y., Fattebert, Jean-Luc, Emigh, Aiyana, and Lightstone, Felice C. A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations. United States: N. p., 2015. Web. doi:10.1371/journal.pone.0121092.
Bennion, Brian J., Essiz, Sebnem G., Lau, Edmond Y., Fattebert, Jean-Luc, Emigh, Aiyana, & Lightstone, Felice C. A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations. United States. https://doi.org/10.1371/journal.pone.0121092
Bennion, Brian J., Essiz, Sebnem G., Lau, Edmond Y., Fattebert, Jean-Luc, Emigh, Aiyana, and Lightstone, Felice C. Mon . "A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations". United States. https://doi.org/10.1371/journal.pone.0121092. https://www.osti.gov/servlets/purl/1399705.
@article{osti_1399705,
title = {A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations},
author = {Bennion, Brian J. and Essiz, Sebnem G. and Lau, Edmond Y. and Fattebert, Jean-Luc and Emigh, Aiyana and Lightstone, Felice C.},
abstractNote = {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.},
doi = {10.1371/journal.pone.0121092},
journal = {PLoS ONE},
number = 4,
volume = 10,
place = {United States},
year = {Mon Apr 13 00:00:00 EDT 2015},
month = {Mon Apr 13 00:00:00 EDT 2015}
}

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Works referencing / citing this record:

Identification of new allosteric sites and modulators of AChE through computational and experimental tools
text, January 2018


Identification of new allosteric sites and modulators of AChE through computational and experimental tools
text, January 2018


Potential acetylcholinesterase inhibitors: molecular docking, molecular dynamics, and in silico prediction
journal, February 2017

  • Kiametis, Alessandra S.; Silva, Mônica A.; Romeiro, Luiz A. S.
  • Journal of Molecular Modeling, Vol. 23, Issue 2
  • DOI: 10.1007/s00894-017-3228-9

Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations
journal, June 2017


Computational Studies on Acetylcholinesterases
journal, August 2017


Computational Studies on Acetylcholinesterases
journal, August 2017


Identification of new allosteric sites and modulators of AChE through computational and experimental tools
journal, January 2018

  • Roca, Carlos; Requena, Carlos; Sebastián-Pérez, Víctor
  • Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 33, Issue 1
  • DOI: 10.1080/14756366.2018.1476502

Identification of new allosteric sites and modulators of AChE through computational and experimental tools
text, January 2018