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If an adversary wanted to stop an army in its tracks, a chemical
and biological weapon designed to incapacitate the central nervous
system (CNS) would be devastating to our warfighters. With this in
mind, the Defense Threat Reduction Agency's Joint Science and
Technology Office and the French company CEA are diligently trying
to improve existing medical countermeasures (MCMs) by using
acetylcholinesterase, or AChE, a key enzyme in the nervous system,
to defend against such threats.
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July 25, 2016 - Active site gorge of hAChE phosphonylated by aged
soman. The figure was made from a model of aged hAChE–soman
conjugate. The ligands are represented as balls and sticks and key
active site residues are represented as sticks, carbon in green,
oxygen in red, nitrogen in dark blue. Hydrogen bonds are represented
in black dashed lines. Ser203 and His447 belong to the catalytic
triad. (Image courtesy of Dr. Judith Peters, University Grenoble
Alps, developed under DTRA contract)
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Understanding the chemical nature of organophosphate deactivation
of human acetylcholinesterase (hAChE) in detail allows advancement
of improved medical countermeasures for the protection and treatment
of affected warfighters.
JSTO and CEA are exploring the
effects of non-covalent reversible and covalent irreversible
inhibitors and recently published a study on the molecular dynamic
effects of these inhibitors on hAChE.
Scientists from CEA
performed molecular dynamics studies on inhibited forms of AChE to
examine the effects of inhibition on protein structure. The AChE was
treated with the nerve agent soman to form the covalent and aged
adduct. This subsequently underwent analysis called incoherent
neutron scattering to investigate the molecular dynamics at the
picosecond-nanosecond timescale and examine the non-covalent and
covalent inhibitors. Results showed decreased flexibility of the
inhibited protein attributed to reordering of water molecules within
the structure.
Conversely, AChE treated with Huperzine A, a
reversible, non-covalent inhibitor, showed little to no effect in
structural flexibility when compared to untreated proteins. Thus,
several additive contributions seem responsible for the stiffening
effect of the soman inhibition rather than a single interaction.
The study, published in the Physical Chemistry Chemical Physics,
“Dynamics of human acetylcholinesterase bound to non-covalent and
covalent inhibitors shedding light on changes to the water network
structure,” offers scientists a better understanding of the chemical
nature of organophosphate hAChE.
This research will play an
instrumental role in developing medical countermeasures for
warfighters exposed to deadly nerve agents.
Courtesy Story by
Defense Threat Reduction Agency's Chemical and Biological Technologies Department
(DTRA-CBTD)
Provided
through DVIDS
Copyright 2016
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