A QM/MM study of mechanism of antidote action in reactivation of tabun inhibited AChE (CROSBI ID 564668)
Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Šinko, Goran ; Vinković Vrček, Ivana
engleski
A QM/MM study of mechanism of antidote action in reactivation of tabun inhibited AChE
The world food production is closely related with growing use of pesticides in agriculture. Pesticides based on neurotoxic organophosphorous compounds (OPC) and related chemical warfare agents have long attracted attention of the scientists to the development of efficient antidotes for the poisoning with OPC. OPC inhibit irreversibly acetylcholinesterase (AChE), a key enzyme in cholinergic neurotransmission, by phosphylation. Oximes are in use for reactivation of AChE and regeneration of its catalytic activity as antidotes. To design new reactivators a better understanding of the reactivation process is needed. Our aim was to study the reaction mechanism of reactivation using a QM/MM methodology. We selected the AChE-tabun conjugate since tabun is one of the most potent nerve agent, and very resistant to reactivation. We selected oxime reactivator K027 (4-carbamoyl-1-(3-{; ; ; 4- [(E)-(hydroxyimino)methyl]pyridinium-1-yl}; ; ; propyl)pyridinium bromide) due to its effectiveness in reactivation of tabun or pesticide inhibited AChE. QM/MM approach allows computation of the reaction energy profile for the active site atoms trapped inside the native protein environment. First we modelled reactivation reaction on a truncated system using a quantum mechanical(QM) calculation at the BP86/6-311+G(d, p) level of theory. For the molecular mechanical (MM) part, the CHARMm force field was used. We showed that during reactivation oxime needs to change its position inside active site of AChE to form transition state with AChE-tabun conjugate. Analysis of AChE-tabun-K027 transition state structure identified the critical residues not only for binding of oximes but also for reactivation of enzyme.
organophosphorous compounds; acetylcholinesterase; oxime; reactivation
DOI: 10.1111/j.1742-4658.2010.07680.x
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Podaci o prilogu
261-261.
2010.
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objavljeno
Podaci o matičnoj publikaciji
The FEBS journal
Oxford: Wiley-Blackwell
1742-464X
Podaci o skupu
FEBS Congress : Molecules of Life (35 ; 2010)
poster
26.06.2010-01.07.2010
Göteborg, Švedska