A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

Bennion, Brian J.; Essiz, Sebnem G.; Lau, Edmond Y.; Fattebert, Jean-Luc; Emigh, Aiyana; Lightstone, Felice C.

doi:10.1371/journal.pone.0121092

Title: A Wrench in the Works of Human Acetylcholinesterase: Soman Induced Conformational Changes Revealed by Molecular Dynamics Simulations

Journal Article · Mon Apr 13 00:00:00 EDT 2015 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0121092· OSTI ID:1399705

Bennion, Brian J. ^[1]; Essiz, Sebnem G. ^[2]; Lau, Edmond Y. ^[1]; Fattebert, Jean-Luc ^[1]; Emigh, Aiyana ^[1]; Lightstone, Felice C. ^[1]

Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Kadir Has Univ., Istanbul (Turkey)

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.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1399705

Alternate ID(s):: OSTI ID: 1200900

Report Number(s):: LLNL-JRNL-644163

Journal Information:: PLoS ONE, Vol. 10, Issue 4; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 25 works

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References (83)

Generalized Gradient Approximation Made Simple Perdew, John P.; Burke, Kieron; Ernzerhof, Matthias Physical Review Letters, Vol. 77, Issue 18, p. 3865-3868 https://doi.org/10.1103/PhysRevLett.77.3865	journal	October 1996
Electrostatic steering of substrate to acetylcholinesterase: Analysis of field fluctuations Wlodek, Stanislaw T.; Shen, Tongye; McCammon, J. Andrew Biopolymers, Vol. 53, Issue 3 https://doi.org/10.1002/(SICI)1097-0282(200003)53:3<265::AID-BIP6>3.0.CO;2-N	journal	March 2000
Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: Possible implications for the HI-6 antidote substrate specificity Artursson, Elisabet; Andersson, Per Ola; Akfur, Christine Biochemical Pharmacology, Vol. 85, Issue 9 https://doi.org/10.1016/j.bcp.2013.01.016	journal	May 2013
Peripheral binding site is involved in the neurotrophic activity of acetylcholinesterase Muñoz, Francisco J.; Aldunate, Rebeca; Inestrosa, Nibaldo C. NeuroReport, Vol. 10, Issue 17 https://doi.org/10.1097/00001756-199911260-00029	journal	January 1999
Crystal Structures of Aged Phosphonylated Acetylcholinesterase: Nerve Agent Reaction Products at the Atomic Level ^† ^, ^‡ Millard, Charles B.; Kryger, Gitay; Ordentlich, Arie Biochemistry, Vol. 38, Issue 22 https://doi.org/10.1021/bi982678l	journal	June 1999
Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations Sanson, Benoît; Colletier, Jacques-Philippe; Xu, Yechun Protein Science, Vol. 20, Issue 7 https://doi.org/10.1002/pro.661	journal	June 2011
Aging Mechanism of Soman Inhibited Acetylcholinesterase Sirin, Gulseher Sarah; Zhou, Yanzi; Lior-Hoffmann, Lee The Journal of Physical Chemistry B, Vol. 116, Issue 40 https://doi.org/10.1021/jp307790v	journal	September 2012
Aging of phosphylated human acetylcholinesterase: catalytic processes mediated by aromatic and polar residues of the active centre Shafferman, Avigdor; Ordentlich, Arie; Barak, Dov Biochemical Journal, Vol. 318, Issue 3 https://doi.org/10.1042/bj3180833	journal	September 1996
Structure of HI-6•Sarin-Acetylcholinesterase Determined by X-Ray Crystallography and Molecular Dynamics Simulation: Reactivator Mechanism and Design Ekström, Fredrik; Hörnberg, Andreas; Artursson, Elisabet PLoS ONE, Vol. 4, Issue 6 https://doi.org/10.1371/journal.pone.0005957	journal	June 2009
Novel generalized Born methods Lee, Michael S.; Salsbury, Freddie R.; Brooks, Charles L. The Journal of Chemical Physics, Vol. 116, Issue 24 https://doi.org/10.1063/1.1480013	journal	June 2002
Site-directed mutants designed to test back-door hypotheses of acetylcholinesterase function Faerman, Carlos; Ripoll, Daniel; Bon, Suzanne FEBS Letters, Vol. 386, Issue 1 https://doi.org/10.1016/0014-5793(96)00374-2	journal	May 1996
“Back Door” Opening Implied by the Crystal Structure of a Carbamoylated Acetylcholinesterase ^‡ Bartolucci, Cecilia; Perola, Emanuele; Cellai, Luciano Biochemistry, Vol. 38, Issue 18 https://doi.org/10.1021/bi982723p	journal	May 1999
Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein Sussman, J.; Harel, M.; Frolow, F. Science, Vol. 253, Issue 5022 https://doi.org/10.1126/science.1678899	journal	August 1991
Allosteric Control of Acetylcholinesterase Catalysis by Fasciculin Radić, Zoran; Quinn, Daniel M.; Vellom, Daniel C. Journal of Biological Chemistry, Vol. 270, Issue 35 https://doi.org/10.1074/jbc.270.35.20391	journal	September 1995
The value of novel oximes for treatment of poisoning by organophosphorus compounds Worek, Franz; Thiermann, Horst Pharmacology & Therapeutics, Vol. 139, Issue 2 https://doi.org/10.1016/j.pharmthera.2013.04.009	journal	August 2013
Benchmark Database of Barrier Heights for Heavy Atom Transfer, Nucleophilic Substitution, Association, and Unimolecular Reactions and Its Use to Test Theoretical Methods Zhao, Yan; González-García, Núria; Truhlar, Donald G. The Journal of Physical Chemistry A, Vol. 109, Issue 9 https://doi.org/10.1021/jp045141s	journal	March 2005
How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? Wang, Junmei; Cieplak, Piotr; Kollman, Peter A. Journal of Computational Chemistry, Vol. 21, Issue 12 https://doi.org/10.1002/1096-987X(200009)21:12<1049::AID-JCC3>3.0.CO;2-F	journal	January 2000
CHARMM: The biomolecular simulation program Brooks, B. R.; Brooks, C. L.; Mackerell, A. D. Journal of Computational Chemistry, Vol. 30, Issue 10 https://doi.org/10.1002/jcc.21287	journal	July 2009
Reaction Products of Acetylcholinesterase and VX Reveal a Mobile Histidine in the Catalytic Triad Millard, Charles B.; Koellner, Gertraud; Ordentlich, Arie Journal of the American Chemical Society, Vol. 121, Issue 42 https://doi.org/10.1021/ja992704i	journal	October 1999
Y124 at the peripheral anionic site is important for the reactivation of nerve agent-inhibited acetylcholinesterase by H oximes Luo, Chunyuan; Chambers, Carolyn; Pattabiraman, Nagarajan Biochemical Pharmacology, Vol. 80, Issue 9 https://doi.org/10.1016/j.bcp.2010.07.020	journal	November 2010
Flexibility of Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase: X-ray versus Molecular Dynamics Xu, Yechun; Colletier, Jacques-Philippe; Weik, Martin Biophysical Journal, Vol. 95, Issue 5 https://doi.org/10.1529/biophysj.108.129601	journal	September 2008
Fractional diffusion-limited component of reactions catalyzed by acetylcholinesterase Bazelyansky, Michael; Robey, Ellen; Kirsch, Jack F. Biochemistry, Vol. 25, Issue 1 https://doi.org/10.1021/bi00349a019	journal	January 1986
Crystallographic Snapshots of Nonaged and Aged Conjugates of Soman with Acetylcholinesterase, and of a Ternary Complex of the Aged Conjugate with Pralidoxime ^† Sanson, Benoît; Nachon, Florian; Colletier, Jacques-Philippe Journal of Medicinal Chemistry, Vol. 52, Issue 23 https://doi.org/10.1021/jm900433t	journal	December 2009
Improved Treatment of the Protein Backbone in Empirical Force Fields MacKerell, Alexander D.; Feig, Michael; Brooks, Charles L. Journal of the American Chemical Society, Vol. 126, Issue 3 https://doi.org/10.1021/ja036959e	journal	January 2004
Gates of Enzymes Gora, Artur; Brezovsky, Jan; Damborsky, Jiri Chemical Reviews, Vol. 113, Issue 8 https://doi.org/10.1021/cr300384w	journal	April 2013
The Dynamics of Ligand Barrier Crossing inside the Acetylcholinesterase Gorge Bui, Jennifer M.; Henchman, Richard H.; McCammon, J. Andrew Biophysical Journal, Vol. 85, Issue 4 https://doi.org/10.1016/s0006-3495(03)74651-7	journal	October 2003
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 Greenblatt, Harry M.; Guillou, Catherine; Guénard, Daniel Journal of the American Chemical Society, Vol. 126, Issue 47 https://doi.org/10.1021/ja0466154	journal	December 2004
Stereochemistry and secondary reactions in the irreversible inhibition of serine hydrolases by organophosphorus compounds Kovach, Ildiko M. Journal of Physical Organic Chemistry, Vol. 17, Issue 67 https://doi.org/10.1002/poc.778	journal	May 2004
Simulation of activation free energies in molecular systems Neria, Eyal; Fischer, Stefan; Karplus, Martin The Journal of Chemical Physics, Vol. 105, Issue 5 https://doi.org/10.1063/1.472061	journal	August 1996
The ‘aromatic patch’ of three proximal residues in the human acetylcholinesterase active centre allows for versatile interaction modes with inhibitors Ariel, Naomi; Ordentlich, Arie; Barak, Dov Biochemical Journal, Vol. 335, Issue 1 https://doi.org/10.1042/bj3350095	journal	October 1998
The Molecular Mechanism of Stabilization of Proteins by TMAO and Its Ability to Counteract the Effects of Urea Zou, Qin; Bennion, Brian J.; Daggett, Valerie Journal of the American Chemical Society, Vol. 124, Issue 7 https://doi.org/10.1021/ja004206b	journal	February 2002
Conformational change of proteins arising from normal mode calculations Tama, F.; Sanejouand, Y. -H. Protein Engineering, Design and Selection, Vol. 14, Issue 1 https://doi.org/10.1093/protein/14.1.1	journal	January 2001
MODELING THE BINDING OF CWAs TO AChE AND BuChE Bennion, Brian J.; Lau, Edmond Y.; Fattebert, Jean-Luc Military Medical Science Letters, Vol. 82, Issue 3 https://doi.org/10.31482/mmsl.2013.015	journal	September 2013
Molecular docking study on the “back door” hypothesis for product clearance in acetylcholinesterase Alisaraie, Laleh; Fels, Gregor Journal of Molecular Modeling, Vol. 12, Issue 3 https://doi.org/10.1007/s00894-005-0051-5	journal	December 2005
The “back door” hypothesis for product clearance in acetylcholinesterase challenged by site-directed mutagenesis. Kronman, C.; Ordentlich, A.; Barak, D. Journal of Biological Chemistry, Vol. 269, Issue 45 https://doi.org/10.1016/s0021-9258(18)46859-7	journal	November 1994
Electrooptical measurements demonstrate a large permanent dipole moment associated with acetylcholinesterase Porschke, D.; Créminon, C.; Cousin, X. Biophysical Journal, Vol. 70, Issue 4 https://doi.org/10.1016/S0006-3495(96)79759-X	journal	April 1996
The Alkaline Hydrolysis of isoPropoxy-methyl-phosphoryl Fluoride (Sarin) and some Analogues. Larsson, Lennart; Siitonen, Soini; Skrifvars, Bengt Acta Chemica Scandinavica, Vol. 11 https://doi.org/10.3891/acta.chem.scand.11-1131	journal	January 1957
Free energy landscape for the binding process of Huperzine A to acetylcholinesterase Bai, Fang; Xu, Yechun; Chen, Jing Proceedings of the National Academy of Sciences, Vol. 110, Issue 11 https://doi.org/10.1073/pnas.1301814110	journal	February 2013
Active Site Gating and Substrate Specificity of Butyrylcholinesterase and Acetylcholinesterase: Insights from Molecular Dynamics Simulations Fang, Lei; Pan, Yongmei; Muzyka, Jennifer L. The Journal of Physical Chemistry B, Vol. 115, Issue 27 https://doi.org/10.1021/jp112030p	journal	July 2011
Fasciculin 2 Binds to the Peripheral Site on Acetylcholinesterase and Inhibits Substrate Hydrolysis by Slowing a Step Involving Proton Transfer during Enzyme Acylation Eastman, Jean; Wilson, Erica J.; Cerveñansky, Carlos Journal of Biological Chemistry, Vol. 270, Issue 34 https://doi.org/10.1074/jbc.270.34.19694	journal	August 1995
Crystal structures of acetylcholinesterase in complex with HI-6, Ortho-7 and obidoxime: Structural basis for differences in the ability to reactivate tabun conjugates Ekström, Fredrik; Pang, Yuan-Ping; Boman, Malin Biochemical Pharmacology, Vol. 72, Issue 5 https://doi.org/10.1016/j.bcp.2006.05.027	journal	August 2006
The Protein Data Bank Berman, H. M. Nucleic Acids Research, Vol. 28, Issue 1 https://doi.org/10.1093/nar/28.1.235	journal	January 2000
Amino acid residues involved in the interaction of acetylcholinesterase and butyrylcholinesterase with the carbamates Ro 02-0683 and bambuterol, and with terbutaline Kovarik, Zrinka; Radić, Zoran; Grgas, Branka Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, Vol. 1433, Issue 1-2 https://doi.org/10.1016/S0167-4838(99)00124-7	journal	August 1999
How Does Huperzine A Enter and Leave the Binding Gorge of Acetylcholinesterase? Steered Molecular Dynamics Simulations Xu, Yechun; Shen, Jianhua; Luo, Xiaomin Journal of the American Chemical Society, Vol. 125, Issue 37 https://doi.org/10.1021/ja029775t	journal	September 2003
Nanosecond Dynamics of Acetylcholinesterase Near the Active Center Gorge Boyd, Aileen E.; Dunlop, Cristina S.; Wong, Lilly Journal of Biological Chemistry, Vol. 279, Issue 25 https://doi.org/10.1074/jbc.M401482200	journal	April 2004
Syrian gas attack reinforces need for better anti-sarin drugs Dolgin, Elie Nature Medicine, Vol. 19, Issue 10 https://doi.org/10.1038/nm1013-1194	journal	October 2013
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Semianalytical treatment of solvation for molecular mechanics and dynamics Still, W. Clark; Tempczyk, Anna; Hawley, Ronald C. Journal of the American Chemical Society, Vol. 112, Issue 16 https://doi.org/10.1021/ja00172a038	journal	August 1990
Cooperative binding of DNA and CBF to the Runt domain of the CBF studied via MD simulations Habtemariam, B. Nucleic Acids Research, Vol. 33, Issue 13 https://doi.org/10.1093/nar/gki724	journal	July 2005
Preventing Misfolding of the Prion Protein by Trimethylamine N -Oxide ^† Bennion, Brian J.; DeMarco, Mari L.; Daggett, Valerie Biochemistry, Vol. 43, Issue 41 https://doi.org/10.1021/bi0486379	journal	October 2004
Knowledge-based protein secondary structure assignment Frishman, Dmitrij; Argos, Patrick Proteins: Structure, Function, and Genetics, Vol. 23, Issue 4 https://doi.org/10.1002/prot.340230412	journal	December 1995
Scalable molecular dynamics with NAMD Phillips, James C.; Braun, Rosemary; Wang, Wei Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802 https://doi.org/10.1002/jcc.20289	journal	January 2005
Motional heterogeneity in human acetylcholinesterase revealed by a non-Gaussian model for elastic incoherent neutron scattering Peters, Judith; Kneller, Gerald R. The Journal of Chemical Physics, Vol. 139, Issue 16 https://doi.org/10.1063/1.4825199	journal	October 2013
Evolution of and perspectives on therapeutic approaches to nerve agent poisoning Masson, Patrick Toxicology Letters, Vol. 206, Issue 1 https://doi.org/10.1016/j.toxlet.2011.04.006	journal	September 2011
Substrate and Product Trafficking through the Active Center Gorge of Acetylcholinesterase Analyzed by Crystallography and Equilibrium Binding Bourne, Yves; Radić, Zoran; Sulzenbacher, Gerlind Journal of Biological Chemistry, Vol. 281, Issue 39 https://doi.org/10.1074/jbc.M603018200	journal	July 2006
Structural insights into substrate traffic and inhibition in acetylcholinesterase Colletier, Jacques-Philippe; Fournier, Didier; Greenblatt, Harry M. The EMBO Journal, Vol. 25, Issue 12 https://doi.org/10.1038/sj.emboj.7601175	journal	June 2006
Crystal structures of oxime-bound fenamiphos-acetylcholinesterases: Reactivation involving flipping of the His447 ring to form a reactive Glu334–His447–oxime triad Hörnberg, Andreas; Artursson, Elisabet; Wärme, Rikard Biochemical Pharmacology, Vol. 79, Issue 3 https://doi.org/10.1016/j.bcp.2009.08.027	journal	February 2010
Origin of the Catalytic Power of Acetylcholinesterase: Computer Simulation Studies Fuxreiter, Monika; Warshel, Arieh Journal of the American Chemical Society, Vol. 120, Issue 1 https://doi.org/10.1021/ja972326m	journal	January 1998
Electrostatic attraction by surface charge does not contribute to the catalytic efficiency of acetylcholinesterase. Shafferman, A.; Ordentlich, A.; Barak, D. The EMBO Journal, Vol. 13, Issue 15 https://doi.org/10.1002/j.1460-2075.1994.tb06650.x	journal	August 1994
X-ray Structures of Torpedo californica Acetylcholinesterase Complexed with (+)-Huperzine A and (−)-Huperzine B: Structural Evidence for an Active Site Rearrangement^, Dvir, H.; Jiang, H. L.; Wong, D. M. Biochemistry, Vol. 41, Issue 35 https://doi.org/10.1021/bi020151+	journal	August 2002
Linear scaling first-principles molecular dynamics with controlled accuracy Fattebert, Jean-Luc; Gygi, François Computer Physics Communications, Vol. 162, Issue 1 https://doi.org/10.1016/j.cpc.2004.06.068	journal	September 2004
Long Route or Shortcut? A Molecular Dynamics Study of Traffic of Thiocholine within the Active-Site Gorge of Acetylcholinesterase Xu, Yechun; Colletier, Jacques-Philippe; Weik, Martin Biophysical Journal, Vol. 99, Issue 12 https://doi.org/10.1016/j.bpj.2010.10.047	journal	December 2010
Pathways of ligand clearance in acetylcholinesterase by multiple copy sampling Van Belle, Daniel; De Maria, Leonardo; Iurcu, Gabriela Journal of Molecular Biology, Vol. 298, Issue 4 https://doi.org/10.1006/jmbi.2000.3698	journal	May 2000
Open "back door" in a molecular dynamics simulation of acetylcholinesterase Gilson, M.; Straatsma, T.; McCammon, J. Science, Vol. 263, Issue 5151 https://doi.org/10.1126/science.8122110	journal	March 1994
Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: A chemical chaperone at atomic resolution Bennion, B. J.; Daggett, V. Proceedings of the National Academy of Sciences, Vol. 101, Issue 17 https://doi.org/10.1073/pnas.0308633101	journal	April 2004
Aging of Cholinesterases Phosphylated by Tabun Proceeds through O-Dealkylation Carletti, Eugénie; Li, He; Li, Bin Journal of the American Chemical Society, Vol. 130, Issue 47 https://doi.org/10.1021/ja804941z	journal	November 2008
Gated Diffusion-controlled Reactions McCammon, J. Andrew BMC Biophysics, Vol. 4, Issue 1 https://doi.org/10.1186/2046-1682-4-4	journal	March 2011
A review on cholinesterase inhibitors for Alzheimer’s disease Anand, Preet; Singh, Baldev Archives of Pharmacal Research, Vol. 36, Issue 4 https://doi.org/10.1007/s12272-013-0036-3	journal	February 2013
Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes Worek, Franz; Thiermann, Horst; Szinicz, Ladislaus Biochemical Pharmacology, Vol. 68, Issue 11 https://doi.org/10.1016/j.bcp.2004.07.038	journal	December 2004
Quantitative Assessment of Electrostatic Embedding in Density Functional Theory Calculations of Biomolecular Systems Fattebert, J. -L.; Law, R. J.; Bennion, B. Journal of Chemical Theory and Computation, Vol. 5, Issue 9 https://doi.org/10.1021/ct900209y	journal	July 2009
Acetylcholinesterase: electrostatic steering increases the rate of ligand binding Tan, Raymond C.; Truong, Thanh N.; McCammon, J. Andrew Biochemistry, Vol. 32, Issue 2 https://doi.org/10.1021/bi00053a003	journal	January 1993
Normal mode analysis of macromolecular motions in a database framework: Developing mode concentration as a useful classifying statistic Krebs, W. G.; Alexandrov, Vadim; Wilson, Cyrus A. Proteins: Structure, Function, and Genetics, Vol. 48, Issue 4 https://doi.org/10.1002/prot.10168	journal	August 2002
Analysis of a 10-ns Molecular Dynamics Simulation of Mouse Acetylcholinesterase Tai, Kaihsu; Shen, Tongye; Börjesson, Ulf Biophysical Journal, Vol. 81, Issue 2 https://doi.org/10.1016/S0006-3495(01)75736-0	journal	August 2001
Use of a `caged' analogue to study the traffic of choline within acetylcholinesterase by kinetic crystallography Colletier, Jacques-Philippe; Royant, Antoine; Specht, Alexandre Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 11 https://doi.org/10.1107/s0907444907044472	journal	October 2007
Reaction Pathway and Free-Energy Barrier for Reactivation of Dimethylphosphoryl-Inhibited Human Acetylcholinesterase Liu, Junjun; Zhang, Yingkai; Zhan, Chang-Guo The Journal of Physical Chemistry B, Vol. 113, Issue 50 https://doi.org/10.1021/jp9055335	journal	December 2009
Reaction profiles of the interaction between sarin and acetylcholinesterase and the S203C mutant: Model nucleophiles and QM/MM potential energy surfaces Beck, Jeremy M.; Hadad, Christopher M. Chemico-Biological Interactions, Vol. 187, Issue 1-3 https://doi.org/10.1016/j.cbi.2010.02.012	journal	September 2010
Energy Landscapes of Human Acetylcholinesterase and Its Huperzine A-Inhibited Counterpart Trapp, Marcus; Trovaslet, Marie; Nachon, Florian The Journal of Physical Chemistry B, Vol. 116, Issue 51 https://doi.org/10.1021/jp304704h	journal	December 2012
Small Molecular Products of Dealkylation in Soman-Inhibited Electric Eel Acetylcholinesterase Viragh, Carol; Kovach, Ildiko M.; Pannell, Lewis Biochemistry, Vol. 38, Issue 30 https://doi.org/10.1021/bi991112+	journal	July 1999
Ageing and dealkylation of soman (pinacolylmethylphosphonofluoridate)-inactivated eel cholinesterase Michel, Harry O.; Hackley, Brennie E.; Berkowitz, Lewis Archives of Biochemistry and Biophysics, Vol. 121, Issue 1 https://doi.org/10.1016/0003-9861(67)90006-9	journal	July 1967
Conformation gating as a mechanism for enzyme specificity Zhou, Huan-Xiang; Wlodek, Stanislaw T.; McCammon, J. Andrew Proceedings of the National Academy of Sciences, Vol. 95, Issue 16 https://doi.org/10.1073/pnas.95.16.9280	journal	August 1998
Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design Xu, Yechun; Colletier, Jacques Ph.; Jiang, Hualiang Protein Science, Vol. 17, Issue 4 https://doi.org/10.1110/ps.083453808	journal	April 2008
Turnover Number of Acetylcholinesterase Wilson, Irwin B.; Harrison, M. A. Journal of Biological Chemistry, Vol. 236, Issue 8 https://doi.org/10.1016/S0021-9258(18)64073-6	journal	August 1961
Binding of 125I-fasciculin to rat brain acetylcholinesterase. The complex still binds diisopropyl fluorophosphate Marchot, P.; Khélif, A.; Ji, Y. H. Journal of Biological Chemistry, Vol. 268, Issue 17 https://doi.org/10.1016/S0021-9258(18)31411-X	journal	June 1993

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