title: On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach.
abstract: Acetylcholinesterase (AChE), an enzyme of the serine hydrolase superfamily, is a mediator of signal transmission at cholinergic synapses by catalyzing acetylcholine cleavage into acetate and choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds (like VX). Covalent inhibition of AChE does not revert spontaneously. Known reactivator compounds have limited action in restoring catalytic activity. QM/MM simulations of VX-inhibited AChE reactivation by pralidoxime (2-PAM), a classical reactivator, were performed. These afforded a broad view of the effect of protonation states of active-site residues, and provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM for both protonation states of Glu202 showed that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Because the active site of serine hydrolases is highly conserved, this work provides new insights on the interplay between the catalytic triad residues and this glutamate, newly identified as protonatable.
authors.affiliation: Sorbonne Universités, UPMC UNIV Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place Jussieu, 75252, Paris Cedex 05, France.
authors.forename: Thomas
authors.identifier: 0000-0003-1891-8998
authors.initials: T
authors.lastname: Driant
authors.affiliation: Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 1 Place Général Valérie André, 91223, Brétigny-sur-Orge Cédex, France.
authors.forename: Florian
authors.identifier: 0000-0003-0293-2429
authors.initials: F
authors.lastname: Nachon
authors.affiliation: Sorbonne Universités, UPMC UNIV Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place Jussieu, 75252, Paris Cedex 05, France.
authors.forename: Cyril
authors.identifier: 0000-0003-2416-4467
authors.initials: C
authors.lastname: Ollivier
authors.affiliation: Normandie Université, COBRA, UMR 6014 and FR 3038, Université Rouen-Normandie, INSA Rouen, CNRS, 1 rue Tesnière, 76821, Mont-Saint-Aignan Cedex, France.
authors.forename: Pierre-Yves
authors.identifier: 0000-0001-9094-9778
authors.initials: PY
authors.lastname: Renard
authors.affiliation: Sorbonne Universités, UPMC UNIV Paris 06, Institut Parisien de Chimie Moléculaire, UMR CNRS 8232, Case 229, 4 Place Jussieu, 75252, Paris Cedex 05, France.
authors.forename: Etienne
authors.identifier: 0000-0002-8637-2707
authors.initials: E
authors.lastname: Derat
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D002801:Cholinesterase Reactivators / Q000737:chemistry*; D003198:Computer Simulation; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry; D009946:Organothiophosphorus Compounds / Q000737:chemistry; D011220:Pralidoxime Compounds / Q000737:chemistry; D011522:Protons; D011789:Quantum Theory; D012694:Serine / Q000737:chemistry
chemical_list: D000110:Acetylcholinesterase; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018698:Glutamic Acid; D006639:Histidine; D010755:Organophosphates; D009946:Organothiophosphorus Compounds; D011220:Pralidoxime Compounds; D011522:Protons; D012694:Serine; C009680:VX-agent; C028797:pralidoxime; C009374:tabun
keywords: QM/MM; acetylcholinesterase; computational chemistry; organophosphate; protonation; reactivation