Characterization of a complete cycle of acetylcholinesterase catalysis by ab initio QM/MM modeling

Nemukhin, Alexander V.; Lushchekina, Sofya V.; Bochenkova, Anastasia V.; Golubeva, Anna A.; Varfolomeev, S. D.

doi:10.1007/s00894-008-0287-y

Cited by 70 publications

(41 citation statements)

References 39 publications

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“…Therefore, due to the stabilizing effect of Glu325 on the imidazolium cation, the one proton mechanism is ener getically more favorable. These results are in complete agreement with the results of our previous calculations of the hydrolysis in the active site of acetylcholinesterase, which is similar in the structure and the mechanism of hydrolysis to BuChE, 13 and also with other results of mod eling of the mechanisms of hydrolysis of serine proteases 28 and carboxypeptidases. 10 To sum up, the results of QM/MM simulation showed that the Asp70Gly single mutation of butyrylcholinest erase does not lead to the qualitatively different energy profile of the hydrolysis of succinylcholine for the acyla tion step compared to the native enzyme.…”

Section: Resultssupporting

confidence: 93%

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

et al. 2010

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Section: Resultssupporting

confidence: 93%

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

et al. 2010

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“…40 However, a series of recent studies demonstrated that at a low substrate concentration, hydrolysis of ACh is rate-determined by the acylation reaction, 2, 41, 46 which is consistent with our recently reported study. 47 Despite extensive studies on the catalytic mechanisms of cholinesterase-catalyzed hydrolysis of ACh/ATCh, 1-2, 15, 27-30, 33-34, 36, 38, 48-50 questions remain for the mechanism of the substrate activation for BChE-catalyzed hydrolysis of ACh/ATCh. For example, what is the main factor leading to the observed substrate activation effect?…”

Section: Introductionmentioning

confidence: 99%

Reaction Pathway and Free Energy Profiles for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylthiocholine

et al. 2012

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The catalytic mechanism for butyrylcholineserase (BChE)-catalyzed hydrolysis of acetylthiocholine (ATCh) has been studied by performing pseudobond first-principles quantum mechanical/molecular mechanical-free energy (QM/MM-FE) calculations on both acylation and deacylation of BChE. Additional quantum mechanical (QM) calculations have been carried out, along with the QM/MM-FE calculations, to understand the known substrate activation effect on the enzymatic hydrolysis of ATCh. It has been shown that the acylation of BChE with ATCh consists of two reaction steps including the nucleophilic attack on the carbonyl carbon of ATCh and the dissociation of thiocholine ester. The deacylation stage includes nucleophilic attack of a water molecule on the carboxyl carbon of substrate and dissociation between the carboxyl carbon of substrate and hydroxyl oxygen of Ser198 side chain. QM/MM-FE calculation results reveal that the acylation of BChE is rate-determining. It has also been demonstrated that an additional substrate molecule binding to the peripheral anionic site (PAS) of BChE is responsible for the substrate activation effect. In the presence of this additional substrate molecule at PAS, the calculated free energy barrier for the acylation stage (rate-determining step) is decreased by ~1.7 kcal/mol. All of our computational predictions are consistent with available experimental kinetic data. The overall free energy barriers calculated for BChE-catalyzed hydrolysis of ATCh at regular hydrolysis phase and substrate activation phase are ~13.6 and ~11.9 kcal/mol, respectively, which are in reasonable agreement with the corresponding experimentally-derived activation free energies of 14.0 kcal/mol (for regular hydrolysis phase) and 13.5 kcal/mol (for substrate activation phase). .

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“…[2][3][4][5][6] Several molecular modelling studies available in literature point out to important features on the oximes structures that could be very useful to guide experimental research on this issue. [7][8][9][10][11][12][13][14][15][16][17][18][19] In a former work 4 …”

Section: Introductionmentioning

confidence: 99%

Molecular aspects of the reactivation process of acetylcholinesterase inhibited by cyclosarin

Matos¹,

Mancini²,

Cunha³

et al. 2011

J. Braz. Chem. Soc.

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No presente trabalho foi aplicada uma metodologia teórica desenvolvida em um trabalho anterior que utiliza os programas Molegro ® e Spartan ® para avaliar as constantes cinéticas de associação e reativação de oximas, em relação a resultados in vitro previamente reportados na literatura. Como observado antes, os resultados mostraram boa correlação entre as energias livres teóricas de ligação das oximas e os dados experimentais, corroborando a metodologia como adequada para a predição de parâmetros cinéticos e termodinâmicos, os quais podem ser úteis para o planejamento e seleção de novas e mais efetivas oximas.In this work we applied a theoretical methodology developed in a former work, using the Molegro ® and Spartan ® softwares, to evaluate the association and kinetic reactivation constants of oximes, facing in vitro data previously reported in the literature. As reported before, results showed a good agreement between the theoretical binding free energies of the oximes and experimental data, corroborating the methodology as suitable for the prediction of kinetic and thermodynamic parameters that might be helpful for the design and selection of new and more effective oximes. Keywords: acetylcholinesterase, QM/MM, chemical mechanism of reactivation, neurotoxic agents IntroductionThe action of the nerve agents 1,2 as inhibitors of the enzyme acetylcholinesterase (AChE) stops the hydrolysis of the neurotransmitter acetylcholine and can lead to an irreversible inhibition of this enzyme (aging) thus triggering the cholinergic syndrome.3 To avoid this it's necessary a nucleophile, like an oxime, whose hydroxyl group is believed to be able to remove the nerve agent from the active site and reactivate AChE (Scheme 1). This reactivation reaction (illustrated in equation 1) involves, first, the association of the oxime to the inhibited enzyme (EIOx) and then the reactivation of the enzyme by the leaving of the oxime complexed to the neurotoxic agent (I-Ox).Where K R and k r are the dissociation constants, which represent the affinity of oximes for the inhibited AChE, and the rate constant for the decomposition of the stable enzyme-inhibitor-reactivator complex, respectively. 4,5The literature reports many structurally different oximes able to perform the reactivation of AChE inhibited by several different nerve agents, but one structure able to act efficiently against all the existing neurotoxic agents has not yet been reported 4,5 and oximes that are efficient against one specific nerve agent can be completely ineffective with another.2-6 Several molecular modelling studies available in literature point out to important features on the oximes structures that could be very useful to guide experimental research on this issue. [7][8][9][10][11][12][13][14][15][16][17][18][19] In a former work 4 we have Methodology Ligands data set and docking energy calculationsThe in vitro data of K R and k r for the oximes studied in this work (Figure 1) regarding AChE inhibited by cyclosarin, were reported by Kassa et al. 5 Crystallogr...

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Characterization of a complete cycle of acetylcholinesterase catalysis by ab initio QM/MM modeling

Cited by 70 publications

References 39 publications

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

Modeling of the mechanism of hydrolysis of succinylcholine in the active site of native and modified (Asp70Gly) human butyrylcholinesterase

Reaction Pathway and Free Energy Profiles for Butyrylcholinesterase-Catalyzed Hydrolysis of Acetylthiocholine

Molecular aspects of the reactivation process of acetylcholinesterase inhibited by cyclosarin

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