skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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];  [3]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  2. Kadir Has Univ., Istanbul (Turkey)
  3. Wake Forest Univ., Winston-Salem, NC (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1200900
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, Lightstone, Felice C., and Salsbury , Jr, Freddie. 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., & Salsbury , Jr, Freddie. A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations. United States. doi:10.1371/journal.pone.0121092.
Bennion, Brian J., Essiz, Sebnem G., Lau, Edmond Y., Fattebert, Jean -Luc, Emigh, Aiyana, Lightstone, Felice C., and Salsbury , Jr, Freddie. Mon . "A wrench in the works of human acetylcholinesterase: Soman induced conformational changes revealed by molecular dynamics simulations". United States. doi:10.1371/journal.pone.0121092. https://www.osti.gov/servlets/purl/1200900.
@article{osti_1200900,
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. and Salsbury , Jr, Freddie},
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 = {2015},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 8 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Reaction Products of Acetylcholinesterase and VX Reveal a Mobile Histidine in the Catalytic Triad
journal, October 1999

  • Millard, Charles B.; Koellner, Gertraud; Ordentlich, Arie
  • Journal of the American Chemical Society, Vol. 121, Issue 42
  • DOI: 10.1021/ja992704i

A review on cholinesterase inhibitors for Alzheimer’s disease
journal, February 2013


The value of novel oximes for treatment of poisoning by organophosphorus compounds
journal, August 2013


Syrian gas attack reinforces need for better anti-sarin drugs
journal, October 2013


Crystal Structures of Aged Phosphonylated Acetylcholinesterase:  Nerve Agent Reaction Products at the Atomic Level ,
journal, June 1999

  • Millard, Charles B.; Kryger, Gitay; Ordentlich, Arie
  • Biochemistry, Vol. 38, Issue 22
  • DOI: 10.1021/bi982678l

Evolution of and perspectives on therapeutic approaches to nerve agent poisoning
journal, September 2011


Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes
journal, December 2004

  • Worek, Franz; Thiermann, Horst; Szinicz, Ladislaus
  • Biochemical Pharmacology, Vol. 68, Issue 11
  • DOI: 10.1016/j.bcp.2004.07.038

Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein
journal, August 1991


VMD: Visual molecular dynamics
journal, February 1996


Molecular docking study on the “back door” hypothesis for product clearance in acetylcholinesterase
journal, December 2005


Fractional diffusion-limited component of reactions catalyzed by acetylcholinesterase
journal, January 1986

  • Bazelyansky, Michael; Robey, Ellen; Kirsch, Jack F.
  • Biochemistry, Vol. 25, Issue 1
  • DOI: 10.1021/bi00349a019

Acetylcholinesterase: electrostatic steering increases the rate of ligand binding
journal, January 1993

  • Tan, Raymond C.; Truong, Thanh N.; McCammon, J. Andrew
  • Biochemistry, Vol. 32, Issue 2
  • DOI: 10.1021/bi00053a003

Electrostatic attraction by surface charge does not contribute to the catalytic efficiency of acetylcholinesterase.
journal, August 1994


Electrooptical measurements demonstrate a large permanent dipole moment associated with acetylcholinesterase
journal, April 1996


Electrostatic steering of substrate to acetylcholinesterase: Analysis of field fluctuations
journal, March 2000


Peripheral binding site is involved in the neurotrophic activity of acetylcholinesterase
journal, January 1999


Analysis of a 10-ns Molecular Dynamics Simulation of Mouse Acetylcholinesterase
journal, August 2001


Reaction profiles of the interaction between sarin and acetylcholinesterase and the S203C mutant: Model nucleophiles and QM/MM potential energy surfaces
journal, September 2010


Amino acid residues involved in the interaction of acetylcholinesterase and butyrylcholinesterase with the carbamates Ro 02-0683 and bambuterol, and with terbutaline
journal, August 1999

  • Kovarik, Zrinka; Radić, Zoran; Grgas, Branka
  • Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, Vol. 1433, Issue 1-2
  • DOI: 10.1016/S0167-4838(99)00124-7

Y124 at the peripheral anionic site is important for the reactivation of nerve agent-inhibited acetylcholinesterase by H oximes
journal, November 2010

  • Luo, Chunyuan; Chambers, Carolyn; Pattabiraman, Nagarajan
  • Biochemical Pharmacology, Vol. 80, Issue 9
  • DOI: 10.1016/j.bcp.2010.07.020

Structural insights into substrate traffic and inhibition in acetylcholinesterase
journal, June 2006

  • Colletier, Jacques-Philippe; Fournier, Didier; Greenblatt, Harry M.
  • The EMBO Journal, Vol. 25, Issue 12
  • DOI: 10.1038/sj.emboj.7601175

Substrate and Product Trafficking through the Active Center Gorge of Acetylcholinesterase Analyzed by Crystallography and Equilibrium Binding
journal, July 2006

  • Bourne, Yves; Radić, Zoran; Sulzenbacher, Gerlind
  • Journal of Biological Chemistry, Vol. 281, Issue 39
  • DOI: 10.1074/jbc.M603018200

Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations
journal, June 2011

  • Sanson, Benoît; Colletier, Jacques-Philippe; Xu, Yechun
  • Protein Science, Vol. 20, Issue 7
  • DOI: 10.1002/pro.661

Gates of Enzymes
journal, April 2013

  • Gora, Artur; Brezovsky, Jan; Damborsky, Jiri
  • Chemical Reviews, Vol. 113, Issue 8
  • DOI: 10.1021/cr300384w

Gated Diffusion-controlled Reactions
journal, March 2011


Use of a `caged' analogue to study the traffic of choline within acetylcholinesterase by kinetic crystallography
journal, October 2007

  • Colletier, Jacques-Philippe; Royant, Antoine; Specht, Alexandre
  • Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 11
  • DOI: 10.1107/S0907444907044472

Active Site Gating and Substrate Specificity of Butyrylcholinesterase and Acetylcholinesterase: Insights from Molecular Dynamics Simulations
journal, July 2011

  • Fang, Lei; Pan, Yongmei; Muzyka, Jennifer L.
  • The Journal of Physical Chemistry B, Vol. 115, Issue 27
  • DOI: 10.1021/jp112030p

Flexibility of Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase: X-ray versus Molecular Dynamics
journal, September 2008


Conformation gating as a mechanism for enzyme specificity
journal, August 1998

  • Zhou, Huan-Xiang; Wlodek, Stanislaw T.; McCammon, J. Andrew
  • Proceedings of the National Academy of Sciences, Vol. 95, Issue 16
  • DOI: 10.1073/pnas.95.16.9280

How Does Huperzine A Enter and Leave the Binding Gorge of Acetylcholinesterase? Steered Molecular Dynamics Simulations
journal, September 2003

  • Xu, Yechun; Shen, Jianhua; Luo, Xiaomin
  • Journal of the American Chemical Society, Vol. 125, Issue 37
  • DOI: 10.1021/ja029775t

Free energy landscape for the binding process of Huperzine A to acetylcholinesterase
journal, February 2013

  • Bai, Fang; Xu, Yechun; Chen, Jing
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 11
  • DOI: 10.1073/pnas.1301814110

The Dynamics of Ligand Barrier Crossing inside the Acetylcholinesterase Gorge
journal, October 2003


Pathways of ligand clearance in acetylcholinesterase by multiple copy sampling
journal, May 2000

  • Van Belle, Daniel; De Maria, Leonardo; Iurcu, Gabriela
  • Journal of Molecular Biology, Vol. 298, Issue 4
  • DOI: 10.1006/jmbi.2000.3698

Open "back door" in a molecular dynamics simulation of acetylcholinesterase
journal, March 1994


“Back Door” Opening Implied by the Crystal Structure of a Carbamoylated Acetylcholinesterase
journal, May 1999

  • Bartolucci, Cecilia; Perola, Emanuele; Cellai, Luciano
  • Biochemistry, Vol. 38, Issue 18
  • DOI: 10.1021/bi982723p

Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase
journal, December 2010

  • Xu, Yechun; Colletier, Jacques-Philippe; Weik, Martin
  • Biophysical Journal, Vol. 99, Issue 12
  • DOI: 10.1016/j.bpj.2010.10.047

Site-directed mutants designed to test back-door hypotheses of acetylcholinesterase function
journal, May 1996


Nanosecond Dynamics of Acetylcholinesterase Near the Active Center Gorge
journal, April 2004

  • Boyd, Aileen E.; Dunlop, Cristina S.; Wong, Lilly
  • Journal of Biological Chemistry, Vol. 279, Issue 25
  • DOI: 10.1074/jbc.M401482200

The Complex of a Bivalent Derivative of Galanthamine with Torpedo Acetylcholinesterase Displays Drastic Deformation of the Active-Site Gorge:  Implications for Structure-Based Drug Design
journal, December 2004

  • Greenblatt, Harry M.; Guillou, Catherine; Guénard, Daniel
  • Journal of the American Chemical Society, Vol. 126, Issue 47
  • DOI: 10.1021/ja0466154

The Molecular Mechanism of Stabilization of Proteins by TMAO and Its Ability to Counteract the Effects of Urea
journal, February 2002

  • Zou, Qin; Bennion, Brian J.; Daggett, Valerie
  • Journal of the American Chemical Society, Vol. 124, Issue 7
  • DOI: 10.1021/ja004206b

Preventing Misfolding of the Prion Protein by Trimethylamine N -Oxide
journal, October 2004

  • Bennion, Brian J.; DeMarco, Mari L.; Daggett, Valerie
  • Biochemistry, Vol. 43, Issue 41
  • DOI: 10.1021/bi0486379

Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: A chemical chaperone at atomic resolution
journal, April 2004

  • Bennion, B. J.; Daggett, V.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 17
  • DOI: 10.1073/pnas.0308633101

Structures of recombinant native and E202Q mutant human acetylcholinesterase complexed with the snake-venom toxin fasciculin-II
journal, November 2000

  • Kryger, Gitay; Harel, Michal; Giles, Kurt
  • Acta Crystallographica Section D Biological Crystallography, Vol. 56, Issue 11
  • DOI: 10.1107/S0907444900010659

The Protein Data Bank
journal, January 2000


MODELING THE BINDING OF CWAs TO AChE AND BuChE
journal, September 2013

  • Bennion, Brian J.; Lau, Edmond Y.; Fattebert, Jean-Luc
  • Military Medical Science Letters, Vol. 82, Issue 3
  • DOI: 10.31482/mmsl.2013.015

Generalized Gradient Approximation Made Simple
journal, October 1996

  • Perdew, John P.; Burke, Kieron; Ernzerhof, Matthias
  • Physical Review Letters, Vol. 77, Issue 18, p. 3865-3868
  • DOI: 10.1103/PhysRevLett.77.3865

Quantitative Assessment of Electrostatic Embedding in Density Functional Theory Calculations of Biomolecular Systems
journal, July 2009

  • Fattebert, J. -L.; Law, R. J.; Bennion, B.
  • Journal of Chemical Theory and Computation, Vol. 5, Issue 9
  • DOI: 10.1021/ct900209y

Linear scaling first-principles molecular dynamics with controlled accuracy
journal, September 2004


Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime
journal, December 2009

  • Sanson, Benoît; Nachon, Florian; Colletier, Jacques-Philippe
  • Journal of Medicinal Chemistry, Vol. 52, Issue 23
  • DOI: 10.1021/jm900433t

Scalable molecular dynamics with NAMD
journal, January 2005

  • Phillips, James C.; Braun, Rosemary; Wang, Wei
  • Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
  • DOI: 10.1002/jcc.20289

Improved Treatment of the Protein Backbone in Empirical Force Fields
journal, January 2004

  • MacKerell, Alexander D.; Feig, Michael; Brooks, Charles L.
  • Journal of the American Chemical Society, Vol. 126, Issue 3
  • DOI: 10.1021/ja036959e

Simulation of activation free energies in molecular systems
journal, August 1996

  • Neria, Eyal; Fischer, Stefan; Karplus, Martin
  • The Journal of Chemical Physics, Vol. 105, Issue 5
  • DOI: 10.1063/1.472061

Knowledge-based protein secondary structure assignment
journal, December 1995

  • Frishman, Dmitrij; Argos, Patrick
  • Proteins: Structure, Function, and Genetics, Vol. 23, Issue 4
  • DOI: 10.1002/prot.340230412

Cooperative binding of DNA and CBF  to the Runt domain of the CBF  studied via MD simulations
journal, July 2005


Novel generalized Born methods
journal, June 2002

  • Lee, Michael S.; Salsbury, Freddie R.; Brooks, Charles L.
  • The Journal of Chemical Physics, Vol. 116, Issue 24
  • DOI: 10.1063/1.1480013

Semianalytical treatment of solvation for molecular mechanics and dynamics
journal, August 1990

  • Still, W. Clark; Tempczyk, Anna; Hawley, Ronald C.
  • Journal of the American Chemical Society, Vol. 112, Issue 16
  • DOI: 10.1021/ja00172a038

CHARMM: The biomolecular simulation program
journal, July 2009

  • Brooks, B. R.; Brooks, C. L.; Mackerell, A. D.
  • Journal of Computational Chemistry, Vol. 30, Issue 10
  • DOI: 10.1002/jcc.21287

Conformational change of proteins arising from normal mode calculations
journal, January 2001

  • Tama, F.; Sanejouand, Y. -H.
  • Protein Engineering, Design and Selection, Vol. 14, Issue 1
  • DOI: 10.1093/protein/14.1.1

Normal mode analysis of macromolecular motions in a database framework: Developing mode concentration as a useful classifying statistic
journal, August 2002

  • Krebs, W. G.; Alexandrov, Vadim; Wilson, Cyrus A.
  • Proteins: Structure, Function, and Genetics, Vol. 48, Issue 4
  • DOI: 10.1002/prot.10168

Origin of the Catalytic Power of Acetylcholinesterase:  Computer Simulation Studies
journal, January 1998

  • Fuxreiter, Monika; Warshel, Arieh
  • Journal of the American Chemical Society, Vol. 120, Issue 1
  • DOI: 10.1021/ja972326m

The Alkaline Hydrolysis of isoPropoxy-methyl-phosphoryl Fluoride (Sarin) and some Analogues.
journal, January 1957


Benchmark Database of Barrier Heights for Heavy Atom Transfer, Nucleophilic Substitution, Association, and Unimolecular Reactions and Its Use to Test Theoretical Methods
journal, March 2005

  • Zhao, Yan; González-García, Núria; Truhlar, Donald G.
  • The Journal of Physical Chemistry A, Vol. 109, Issue 9
  • DOI: 10.1021/jp045141s

Aging Mechanism of Soman Inhibited Acetylcholinesterase
journal, September 2012

  • Sirin, Gulseher Sarah; Zhou, Yanzi; Lior-Hoffmann, Lee
  • The Journal of Physical Chemistry B, Vol. 116, Issue 40
  • DOI: 10.1021/jp307790v

Reaction Pathway and Free-Energy Barrier for Reactivation of Dimethylphosphoryl-Inhibited Human Acetylcholinesterase
journal, December 2009

  • Liu, Junjun; Zhang, Yingkai; Zhan, Chang-Guo
  • The Journal of Physical Chemistry B, Vol. 113, Issue 50
  • DOI: 10.1021/jp9055335

Ageing and dealkylation of soman (pinacolylmethylphosphonofluoridate)-inactivated eel cholinesterase
journal, July 1967

  • Michel, Harry O.; Hackley, Brennie E.; Berkowitz, Lewis
  • Archives of Biochemistry and Biophysics, Vol. 121, Issue 1
  • DOI: 10.1016/0003-9861(67)90006-9

Aging of phosphylated human acetylcholinesterase: catalytic processes mediated by aromatic and polar residues of the active centre
journal, September 1996

  • Shafferman, Avigdor; Ordentlich, Arie; Barak, Dov
  • Biochemical Journal, Vol. 318, Issue 3
  • DOI: 10.1042/bj3180833

Stereochemistry and secondary reactions in the irreversible inhibition of serine hydrolases by organophosphorus compounds
journal, May 2004

  • Kovach, Ildiko M.
  • Journal of Physical Organic Chemistry, Vol. 17, Issue 67
  • DOI: 10.1002/poc.778

Aging of Cholinesterases Phosphylated by Tabun Proceeds through O-Dealkylation
journal, November 2008

  • Carletti, Eugénie; Li, He; Li, Bin
  • Journal of the American Chemical Society, Vol. 130, Issue 47
  • DOI: 10.1021/ja804941z

Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: Possible implications for the HI-6 antidote substrate specificity
journal, May 2013

  • Artursson, Elisabet; Andersson, Per Ola; Akfur, Christine
  • Biochemical Pharmacology, Vol. 85, Issue 9
  • DOI: 10.1016/j.bcp.2013.01.016

Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad
journal, February 2010

  • Hörnberg, Andreas; Artursson, Elisabet; Wärme, Rikard
  • Biochemical Pharmacology, Vol. 79, Issue 3
  • DOI: 10.1016/j.bcp.2009.08.027

Motional heterogeneity in human acetylcholinesterase revealed by a non-Gaussian model for elastic incoherent neutron scattering
journal, October 2013

  • Peters, Judith; Kneller, Gerald R.
  • The Journal of Chemical Physics, Vol. 139, Issue 16
  • DOI: 10.1063/1.4825199

Fasciculin 2 Binds to the Peripheral Site on Acetylcholinesterase and Inhibits Substrate Hydrolysis by Slowing a Step Involving Proton Transfer during Enzyme Acylation
journal, August 1995

  • Eastman, Jean; Wilson, Erica J.; Cerveñansky, Carlos
  • Journal of Biological Chemistry, Vol. 270, Issue 34
  • DOI: 10.1074/jbc.270.34.19694

Allosteric Control of Acetylcholinesterase Catalysis by Fasciculin
journal, September 1995

  • Radić, Zoran; Quinn, Daniel M.; Vellom, Daniel C.
  • Journal of Biological Chemistry, Vol. 270, Issue 35
  • DOI: 10.1074/jbc.270.35.20391

    Works referencing / citing this record:

    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