Chemistry Reference
In-Depth Information
highly.preferred.intramolecular.hydrogen.bonds.occur.between.lysine.and.glutamate.
residues..However,.the.only.intramolecular.hydrogen.bond.in.common.between.the.
wild-type. and. A53T. mutant. is. between. residues. 102. and. 105.. While. majority. of.
the.intramolecular.hydrogen.bonds.present.in.the.wild-type.in.the.gas.phase.were.
between.residues.that.are.not.normally.close.to.one.another,.in.the.A53T.mutant.a.
majority.of.the.hydrogen.bonds.present.are.between.residues.that.are.no.more.than.
10.residues.apart..Interestingly,.the.mutation.at.residue.53.from.an.alanine.to.a.threo-
nine. results. in. the. formation. of. an. intramolecular. hydrogen. bond.. Intuitively,. one.
would.assume.that.mutation.of.only.one.residue.would.not.cause.a.signiicant.struc-
tural.change.but.as.seen.earlier,.the.result.is.vastly.different..As.discussed.earlier,.the.
wild-type.protein.in.the.gas.phase.expands.the.coil/turn.region,.linking.the.N-helix.
and.C-helix.from.residues.35.to.44.to.residues.35-52..In.the.case.of.the.A53T.mutant,.
the.intramolecular.hydrogen-bond.formation.as.a.result.of.the.mutation.plays.a.simi-
lar.role.to.the.threonine.intramolecular.hydrogen-bonds.present.in.the.wild-type.in.
aqueous.solution.by.stabilizing.α-helix.conformation.and.preventing.the.movement.
of.the.structure.into.the.wild-type.conformation.
As. seen. in. the. wild-type. simulations,. the. intramolecular. hydrogen. bonds. pres-
ent.in.the.gas-phase.and.in.aqueous.solution.are.very.different..The.only.intramo-
lecular.hydrogen.bonds.that.appear.both.in.the.gas.phase.and.in.water.are.between.
residues.134.and.137.and.the.one.intramolecular.hydrogen.bond.formed.due.to.the.
mutation.between.residues.53.and.49..The.majority.of.the.intramolecular.hydrogen.
bonds,.and.the.most.preferred.ones,.observed.in.the.A53T.mutant.structure.in.aque-
ous. solution. are. between. hydroxyl. hydrogens. of. threonine. residues. and. backbone.
carboxyl.oxygens.separated.by.three.residues.in.the.α-helical.sections.of.the.protein.
that.further.stabilize.the.α-helical.conformation..In.addition,.many.of.these.struc-
turally.stabilizing.threonine.intramolecular.hydrogen.bonds.are.also.present.in.the.
wild-type.structure..Unlike.the.gas-phase.structures,.the.wild-type.and.A53T.mutant.
α-synucleins.have.similar.hydrogen.bonding.and.conformation.in.aqueous.solution..
Our.results.are.similar.to.the.studies.of.Perlmutter.et.al..that.showed.that.the.A53T.
mutation. results. in. an. intramolecular. hydrogen-bond. with. the. carboxyl. oxygen. on.
residue.49.when.interacting.with.an.SDS.micelle.or.lipid.bilayer.
2
.Here.we.provide.
more.detailed.analyses.of.these.conigurational.changes..As.shown.in.our.studies,.
this. hydrogen. bond. is. also. found. in. the. aqueous. solution. simulation. of. the. A53T.
mutant.and.is.in.fact.the.most.preferred.hydrogen.bond.
As.shown.earlier,.hydration.can.have.a.signiicant.impact.on.the.protein.structure.
by. affecting. the. intermolecular. interactions.. However,. there. are. very. few. experi-
mental.methods.that.can.determine.the.effects.of.hydration.on.protein.structure..A.
recent.publication.by.Silva.and.Foguel.nicely.summarizes.how.hydration.character-
istics.are.studied.experimentally.and.what.effects.can.be.seen.in.protein.structure.
39
.
In. order. to. investigate. hydration. properties. experimentally,. hydrostatic. pressure.
techniques.are.used.
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.Essentially,.the.protein.becomes.more.solvated.than.it.would.
be.natively.due.to.increased.water.pressure,.and.this.increased.solvation.denatures.
the.protein.by.forcing.water.into.the.normally.hydrophobic.cores.of.the.proteins.
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In. the. case. of. α-synuclein,. ibrils. are. subjected. to. hydrostatic. pressure. that. dena-
tures.the.ibril.structure.and.as.the.pressure.is.reduced,.ibrillation.reoccurs.slowly.
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