Naslov
A QM/MM study of mechanism of antidote action in reactivation of tabun inhibited AChE

Autori
Šinko, Goran ; Vinković Vrček, Ivana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Abstracts of the 35th FEBS Congress : Molecules of Life ; u: The FEBS Journal 277 (2010) (S1) ; Poster Presentations 37-271 ; E5 – Catalytic Mechanisms, E5.06 / - Oxford : Wiley-Blackwell, 2010, 261-261

Skup
FEBS Congress : Molecules of Life (35 ; 2010)

Mjesto i datum
Göteborg, Švedska, 26.06.2010. - 01.07.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
organophosphorous compounds; acetylcholinesterase; oxime; reactivation

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

Napomena
DOI: 10.1111/j.1742-4658.2010.07680.x

POVEZANOST RADA