Chemistry Reference
In-Depth Information
of.water..Experimental.studies.are.usually.limited.to.providing.direct.information.
about.the.local.structure.of.the.solvent.molecules.around.the.biomolecules.and.their.
impact.on.the.structure.and.conformation.of.these.biomolecules..In.general,.x-ray.and.
neutron.diffraction.measurements.have.been.useful.in.providing.structural.informa-
tion..However,.these.measurements.yield.radial.distribution.functions.(RDF).that.are.
spherically.averaged.to.reduce.the.amount.of.noise.in.the.distribution.functions.from.
the. experimental. data
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. and. thus. the. anisotropic. and. asymmetric. character. of. the.
biomolecules.is.lost..X-ray.and.neutron.diffraction.measurements.also.only.provide.
information.on.the.irst.solvation.shell,.which.are.the.water.molecules.coordinated.to.
the.protein.
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.In.addition,.nuclear.magnetic.resonance.(NMR),.Raman,.and.infrared.
spectroscopy.measurements.can.provide.information.about.the.structure.and.confor-
mation.of.aqueous.biomolecules;.however,.of.these.three.techniques,.only.NMR.is.
capable.of.detecting.the.coordination.of.water.molecules.to.a.biomolecule.
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.While.
the.detection.of.water.molecules.is.possible.with.NMR,.the.process.is.still.dificult.
and.only.water.molecules.within.5.Å.(the.irst.coordination.shell).of.the.protein.can.
be.detected.
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One.experimental.technique.that.attempts.to.investigate.the.impact.of.water.on.
protein. structure. involves. the. use. of. hydrostatic. pressure.
38,39
. This. technique. was.
developed. in. an. effort. to. conirm. the. results. obtained. by. theoretical. studies.
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. By.
subjecting.proteins.in.an.aqueous.environment.to.high.pressure,.water.is.forced.into.
the.normally.hydrophobic.core.of.these.proteins.causing.a.partial.or.complete.dis-
ruption. of. the. native. observed. structure. of. the. proteins.
38,39
. Once. the. pressure. is.
released,.the.refolding.of.the.protein.can.be.observed.using.high-pressure.NMR.and.
luorescence.spectroscopies.and.a.folding.mechanism.can.be.proposed.
38,39
In.the.case.of.hydrostatic.pressure.studies.of.synuclein,.limited.data.is.available.
and.the.only.studies.performed.thus.far.have.been.on.α-synuclein.ibrils.
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.Alpha-
synuclein.ibrils.subjected.to.high.hydrostatic.pressure.are.dissociated.into.soluble.
forms.and.then.monitored.as.ibrillogenesis.occurs.so.that.a.ibrillation.mechanism.
can.be.determined.
39
.Through.these.studies,.researchers.have.found.that.the.mutant.
forms.(A53T.and.A30P).of.the.α-synuclein.proteins.are.more.inclined.to.denatur-
ation. by. high. pressure. than. the. wild-type. form.
39
. It. has. been. proposed. that. this.
experimental. result. relates. to. the. hypothesis. that. it. is. actually. the. oligomers,. and.
not.the.ibrils.and.aggregates,.that.are.pathogenic.to.cells.
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.Therefore,.in.the.case.
of.the.A53T.and.A30P.mutants.of.α-synuclein,.the.hypothesis.is.that.they.are.more.
soluble.in.oligomer.form.and.thus.more.toxic.to.neurons.in.the.
substantia nigra
.
39
.
Researchers.have.also.found.that.α-synuclein.and.its.mutants.in.aggregate.and.ibril.
form.are.highly.susceptible.to.pressure.denaturation.and,.as.a.result,.hydration.and.
dehydration.effects.may.play.an.important.role.in.α-synuclein.aggregation.and.Lewy.
body.formation.
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Although. this. experimental. technique. does. investigate. the. impact. of. water. on.
protein. structure,. there. are. no. current. hydrostatic. pressure. investigations. into. the.
effect.of.water.on.aggregation.at.a.monomer/early.aggregation.level..Additionally,.
this.technique.is.still.not.capable.of.providing.precise.details.of.the.amino.acids.of.
the. protein. that. are. the. most. and. least. hydrated. at. the. molecular. level.. Currently,.
only.theoretical.studies.are.capable.of.determining.hydration.properties.of.a.protein.
on.such.a.detailed.level..The.combination.of.hydrostatic.pressure.experiments.and.
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