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How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study
journal contribution
posted on 2015-12-17, 04:52 authored by Gulseher
Sarah Sirin, Yingkai ZhangAcetylcholinesterase (AChE) is a
crucial enzyme in the cholinergic
nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic
signals by reducing the effective concentration of ACh in the synaptic
clefts. Organophosphate compounds irreversibly inhibit AChEs, leading
to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella
sampling, a state-of-the-art approach to simulate enzyme reactions,
we have characterized the covalent inhibition mechanism between AChE
and the nerve toxin soman and determined its free energy profile for
the first time. Our results indicate that phosphonylation of the catalytic
serine by soman employs an addition–elimination mechanism,
which is highly associative and stepwise: in the initial addition
step, which is also rate-limiting, His440 acts as a general base to
facilitate the nucleophilic attack of Ser200 on the soman’s
phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate;
in the subsequent elimination step, Try121 of the catalytic gorge
stabilizes the leaving fluorine atom prior to its dissociation from
the active site. Together with our previous characterization of the
aging mechanism of soman inhibited AChE, our simulations have revealed
detailed molecular mechanistic insights into the damaging function
of the nerve agent soman.
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Keywords
nerve cellsnucleophilic attacksynaptic cleftsumbrella samplingbipyrimidal pentacovalentcholinergic nerve systemnerve toxin somanaddition stepelimination stepsynaptic signalsenergy profile440 actsAChAChEenzyme reactionsnerve agent somancovalent inhibition mechanismfluorine atomOrganophosphate compoundsAcetylcholinesterase PhosphonylatedSer 200dynamics simulationshydrolyzes acetylcholineQM
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