二甲基膦酰化抑制的人乙酰胆碱酯酶的重激活反应途径和自由能势垒。
Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.
机构信息
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, People's Republic of China.
出版信息
J Phys Chem B. 2009 Dec 17;113(50):16226-36. doi: 10.1021/jp9055335.
Abstract
The dephosphorylation/reactivation mechanism and the corresponding free-energy profile of the dimethylphosphoryl-inhibited conjugate of human acetylcholinesterase (AChE) has been studied by performing first-principles quantum mechanical/molecular mechanical free-energy (QM/MM-FE) calculations. On the basis of the QM/MM-FE results, for the favorable reaction pathway, the entire dephosphorylation/reactivation process consists of three reaction steps, including the nucleophilic water attack on the P atom, the spatial reorganization of the dimethylphosphoryl group, and the dissociation between the dimethylphosphoryl group and Ser203 of AChE. The overall free-energy barrier for the entire dephosphorylation/reactivation reaction is found to be the free-energy change from the initial reactant to the transition state associated with the spatial reorganization step, and the calculated overall free-energy barrier (20.1 to 23.5 kcal/mol) is reasonably close to the experimentally derived activation free energy of 22.3 kcal/mol. In addition, key amino acid residues and their specific roles in the reaction process have been identified.
摘要
通过执行第一性原理量子力学/分子力学自由能（QM/MM-FE）计算，研究了人乙酰胆碱酯酶（AChE）的二甲基膦酰基抑制共轭物的去磷酸化/再激活机制和相应的自由能谱。基于 QM/MM-FE 结果，对于有利的反应途径，整个去磷酸化/再激活过程包括三个反应步骤，包括亲核水分子对 P 原子的攻击、二甲基膦酰基的空间重排以及二甲基膦酰基与 AChE 的 Ser203 之间的解离。整个去磷酸化/再激活反应的总自由能势垒被发现是从初始反应物到与空间重排步骤相关的过渡态的自由能变化，计算出的总自由能势垒（20.1 至 23.5 kcal/mol）与实验得出的 22.3 kcal/mol 的激活自由能相当接近。此外，还确定了反应过程中的关键氨基酸残基及其特定作用。
相似文献
1
Reaction pathway and free-energy barrier for reactivation of dimethylphosphoryl-inhibited human acetylcholinesterase.二甲基膦酰化抑制的人乙酰胆碱酯酶的重激活反应途径和自由能势垒。
J Phys Chem B. 2009 Dec 17;113(50):16226-36. doi: 10.1021/jp9055335.
2
Assessing the reactivation efficacy of hydroxylamine anion towards VX-inhibited AChE: a computational study.评估羟胺阴离子对VX 抑制的乙酰胆碱酯酶的复活效果：一项计算研究。
J Mol Model. 2012 May;18(5):1801-8. doi: 10.1007/s00894-011-1209-y. Epub 2011 Aug 18.
3
Revealing the importance of linkers in K-series oxime reactivators for tabun-inhibited AChE using quantum chemical, docking and SMD studies.利用量子化学、对接和SMD研究揭示K系列肟类重活化剂中连接基对塔崩抑制的乙酰胆碱酯酶的重要性。
J Comput Aided Mol Des. 2017 Aug;31(8):729-742. doi: 10.1007/s10822-017-0036-3. Epub 2017 Jun 23.
4
Slight difference in the isomeric oximes K206 and K203 makes huge difference for the reactivation of organophosphorus-inhibited AChE: Theoretical and experimental aspects.立体异构体肟 K206 和 K203 的细微差异对有机磷抑制的乙酰胆碱酯酶的重激活产生巨大影响：理论和实验方面。
Chem Biol Interact. 2019 Aug 25;309:108671. doi: 10.1016/j.cbi.2019.05.037. Epub 2019 Jun 15.
5
Quantum chemical and steered molecular dynamics studies for one pot solution to reactivate aged acetylcholinesterase with alkylator oxime.用于用烷基化肟单锅溶液重新激活老化乙酰胆碱酯酶的量子化学和定向分子动力学研究。
Chem Biol Interact. 2014 Nov 5;223:58-68. doi: 10.1016/j.cbi.2014.08.015. Epub 2014 Sep 9.
6
Fundamental reaction mechanism and free energy profile for (-)-cocaine hydrolysis catalyzed by cocaine esterase.可卡因酯酶催化（-）-可卡因水解的基本反应机理和自由能剖面图。
J Am Chem Soc. 2009 Aug 26;131(33):11964-75. doi: 10.1021/ja903990p.
7
Resolving pathways of interaction of mipafox and a sarin analog with human acetylcholinesterase by kinetics, mass spectrometry and molecular modeling approaches.通过动力学、质谱和分子建模方法解析米帕明和沙林类似物与人类乙酰胆碱酯酶的相互作用途径。
Arch Toxicol. 2016 Mar;90(3):603-16. doi: 10.1007/s00204-015-1481-1. Epub 2015 Mar 6.
8
Interactions between acetylcholinesterase, toxic organophosphorus compounds and a short series of structurally related non-oxime reactivators: Analysis of reactivation and inhibition kinetics in vitro.乙酰胆碱酯酶、有毒有机磷化合物与一系列结构相关的非肟类重活化剂之间的相互作用：体外重活化和抑制动力学分析。
Toxicol Lett. 2018 Dec 15;299:218-225. doi: 10.1016/j.toxlet.2018.10.004. Epub 2018 Oct 9.
9
Novel tacrine-pyridinium hybrid reactivators of organophosphorus-inhibited acetylcholinesterase: Synthesis, molecular docking, and in vitro reactivation study.新型他克林-吡啶杂交有机磷抑制乙酰胆碱酯酶复活剂：合成、分子对接及体外复活研究
Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3784-3786. doi: 10.1016/j.bmcl.2018.10.006. Epub 2018 Oct 4.
10
4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase.4-氨基苯醌亚甲醚前体：有效且广谱的非肟类有机磷抑制乙酰胆碱酯酶重活化剂和有机磷老化乙酰胆碱酯酶复活剂。
ACS Chem Neurosci. 2024 May 1;15(9):1813-1827. doi: 10.1021/acschemneuro.4c00011. Epub 2024 Apr 15.
引用本文的文献
1
Study on Spontaneous Reactivation and Aging of Acetylcholinesterase Inhibited by Paraoxon and Malaoxon in Ten Species.对十种物种中被对氧磷和马拉氧磷抑制的乙酰胆碱酯酶的自发复活及老化的研究
Int J Mol Sci. 2023 Sep 18;24(18):14213. doi: 10.3390/ijms241814213.
2
Application of Computational Biology and Artificial Intelligence in Drug Design.计算生物学和人工智能在药物设计中的应用。
Int J Mol Sci. 2022 Nov 5;23(21):13568. doi: 10.3390/ijms232113568.
3
In silico Studies on the Interaction between Mpro and PLpro From SARS-CoV-2 and Ebselen, its Metabolites and Derivatives.计算机模拟研究 SARS-CoV-2 的 Mpro 和 PLpro 与依布硒啉及其代谢物和衍生物的相互作用。
Mol Inform. 2021 Aug;40(8):e2100028. doi: 10.1002/minf.202100028. Epub 2021 May 21.
4
Quantum mechanics implementation in drug-design workflows: does it really help?量子力学在药物设计工作流程中的应用：它真的有帮助吗？
Drug Des Devel Ther. 2017 Aug 31;11:2551-2564. doi: 10.2147/DDDT.S126344. eCollection 2017.
5
Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid.无辅因子氧化酶催化反应的催化机制：尿酸酶催化尿酸氧化和水合反应的反应途径
ACS Catal. 2017 Jul 7;7(7):4623-4636. doi: 10.1021/acscatal.7b00901. Epub 2017 Jun 15.
6
Reaction Pathway for Cocaine Hydrolase-Catalyzed Hydrolysis of (+)-Cocaine.可卡因水解酶催化（+）-可卡因水解的反应途径。
Theor Chem Acc. 2016 Jan;135(1). doi: 10.1007/s00214-015-1788-2. Epub 2015 Dec 28.
7
Fundamental reaction pathway and free energy profile of proteasome inhibition by syringolin A (SylA).丁香皮素A（SylA）抑制蛋白酶体的基本反应途径和自由能分布图。
Org Biomol Chem. 2015 Jun 28;13(24):6857-65. doi: 10.1039/c5ob00737b.
8
A wrench in the works of human acetylcholinesterase: soman induced conformational changes revealed by molecular dynamics simulations.人类乙酰胆碱酯酶工作中的一个棘手问题：分子动力学模拟揭示梭曼诱导的构象变化
PLoS One. 2015 Apr 13;10(4):e0121092. doi: 10.1371/journal.pone.0121092. eCollection 2015.
9
How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study.梭曼如何使乙酰胆碱酯酶磷酰化？从头算量子力学/分子力学分子动力学研究。
J Phys Chem A. 2014 Oct 2;118(39):9132-9. doi: 10.1021/jp502712d. Epub 2014 May 9.
10
Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.通过结合分子动力学模拟和QM/MM-PBSA计算得出的尼古丁类似物抑制细胞色素P450 2A6的结合自由能。
Bioorg Med Chem. 2014 Apr 1;22(7):2149-56. doi: 10.1016/j.bmc.2014.02.037. Epub 2014 Mar 3.
本文引用的文献
1
Tinker 8: Software Tools for Molecular Design.Tinker 8：分子设计软件工具。
J Chem Theory Comput. 2018 Oct 9;14(10):5273-5289. doi: 10.1021/acs.jctc.8b00529. Epub 2018 Sep 19.
2
Most efficient cocaine hydrolase designed by virtual screening of transition states.通过过渡态虚拟筛选设计的最有效的可卡因水解酶。
J Am Chem Soc. 2008 Sep 10;130(36):12148-55. doi: 10.1021/ja803646t. Epub 2008 Aug 19.
3
Modeling the catalysis of anti-cocaine catalytic antibody: competing reaction pathways and free energy barriers.抗可卡因催化抗体催化作用的建模：竞争反应途径和自由能垒
J Am Chem Soc. 2008 Apr 16;130(15):5140-9. doi: 10.1021/ja077972s. Epub 2008 Mar 15.
4
How do SET-domain protein lysine methyltransferases achieve the methylation state specificity? Revisited by Ab initio QM/MM molecular dynamics simulations.SET结构域蛋白赖氨酸甲基转移酶是如何实现甲基化状态特异性的？从头算量子力学/分子力学分子动力学模拟的再探讨。
J Am Chem Soc. 2008 Mar 26;130(12):3806-13. doi: 10.1021/ja075896n. Epub 2008 Mar 1.
5
Structure-and-mechanism-based design and discovery of therapeutics for cocaine overdose and addiction.基于结构与机制的可卡因过量及成瘾治疗药物的设计与发现。
Org Biomol Chem. 2008 Mar 7;6(5):836-43. doi: 10.1039/b716268e. Epub 2007 Dec 5.
6
Free energy perturbation (FEP) simulation on the transition states of cocaine hydrolysis catalyzed by human butyrylcholinesterase and its mutants.关于人丁酰胆碱酯酶及其突变体催化可卡因水解过渡态的自由能微扰（FEP）模拟。
J Am Chem Soc. 2007 Nov 7;129(44):13537-43. doi: 10.1021/ja073724k. Epub 2007 Oct 10.
7
Catalytic mechanism and metal specificity of bacterial peptide deformylase: a density functional theory QM/MM study.细菌肽脱甲酰基酶的催化机制和金属特异性：密度泛函理论QM/MM研究
J Phys Chem B. 2007 Jun 7;111(22):6229-35. doi: 10.1021/jp068657f. Epub 2007 May 16.
8
Crystal structures of acetylcholinesterase in complex with organophosphorus compounds suggest that the acyl pocket modulates the aging reaction by precluding the formation of the trigonal bipyramidal transition state.乙酰胆碱酯酶与有机磷化合物复合物的晶体结构表明，酰基口袋通过阻止三角双锥过渡态的形成来调节老化反应。
Biochemistry. 2007 Apr 24;46(16):4815-25. doi: 10.1021/bi0621361. Epub 2007 Apr 3.
9
Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: the case of histone lysine methyltransferase SET7/9.酶催化的从头算量子力学/分子力学分子动力学模拟：组蛋白赖氨酸甲基转移酶SET7/9的实例
J Phys Chem B. 2007 Apr 12;111(14):3758-64. doi: 10.1021/jp067147i. Epub 2007 Mar 22.
10
A water-mediated and substrate-assisted catalytic mechanism for Sulfolobus solfataricus DNA polymerase IV.嗜热栖热菌DNA聚合酶IV的水介导和底物辅助催化机制。
J Am Chem Soc. 2007 Apr 18;129(15):4731-7. doi: 10.1021/ja068821c. Epub 2007 Mar 22.
Zotero 插件