Chemistry Reference
In-Depth Information
in. comparison. to. the. wild-type. α-synuclein.. This. result. is. similar. to. a. discovery. in.
Alzheimer's.disease.that.led.to.the.development.of.the.pharmaceutical.Solanezumab..
By.determining.what.region.of.the.protein.is.most.likely.involved.in.the.aggregation.
mechanism,.treatments.can.be.designed.to.speciically.target.this.region..A.full.under-
standing.of.the.molecular.mechanism.of.aggregation.permits.identiication.of.the.most.
advantageous.points.of.attack.for.potential.treatments.to.prevent.synuclein.aggregation.
Although.it.may.seem.odd.to.think.that.even.one.intramolecular.interaction.could.
signiicantly.impact.protein.structure,.the.evidence.of.the.effect.of.one.intramolec-
ular. interaction. is. apparent. in. the. differences. between. the. wild-type. and. mutant.
structures..Changing.one.amino.acid.between.the.two.protein.variants.results.in.the.
formation.of.one.hydrogen.bond.that.completely.changes.the.dynamical.structure.of.
the.protein.throughout.the.course.of.the.simulations..Any.intramolecular.interaction.
can.have.a.signiicant.effect.on.the.overall.structure.and,.thus,.the.function.of.the.
protein.in.the.intracellular.environment..Therefore,.if.the.delicate.balance.of.the.cell.
environment.is.altered.in.such.a.way.as.to.allow.more.intramolecular.interactions,.the.
structural.and.chemical.properties.of.that.protein.are.altered,.perhaps.permanently.
However,.the.structural.and.dynamical.differences.in.the.protein.are.not.the.only.
signiicant.indings.in.this.study..The.hydration.characteristics.of.both.the.wild-type.
and.mutant.synucleins.have.also.been.determined..The.hydration.trend.between.the.two.
proteins.is.similar,.but.the.exact.coordination.of.water.molecules.around.the.proteins.
is.different..In.both.proteins,.the.N-.and.C-helix.regions.are.the.least.hydrated.and.the.
C-terminal.tail.is.the.most.hydrated..However,.in.the.wild-type.there.are.some.notable.
exceptions..In.the.coil/turn.connection.between.the.two.helical.regions.of.the.protein,.
residue.41.is.highly.coordinated.compared.to.the.rest.of.the.residues..The.hydration.
at. this. point. explains. the. higher. lexibility. of. the. wild-type. protein. in. the. coil/turn.
region..This.region.is.much.more.lexible.in.the.wild-type.than.in.the.mutant.protein.
and.this.lexibility.could.prevent.the.interaction.of.the.N-terminus.with.the.rest.of.the.
protein,.affecting.the.solubility.and.aggregation.of.the.protein..Additionally,.the.least.
hydrated.residue.in.the.wild-type.is.actually.in.the.C-terminal.tail..The.dehydration.in.
this.region.may.increase.the.stability.and.decrease.the.lexibility.of.the.tail..Neither.of.
these.trends.is.observed.in.the.dynamics.of.the.A53T.mutant..The.lack.of.hydration.at.
the.coil/turn.region.allows.for.greater.interaction.of.the.N-terminus.with.the.rest.of.the.
protein,.perhaps.leading.to.decreased.solubility.and.increased.aggregation.
In.looking.at.the.overall.differences.in.the.coordination.numbers.of.water.mol-
ecules.for.both.proteins,.the.A53T.mutant.is.less.hydrated.than.the.wild-type.protein..
This.difference.indicates.that.A53T.is.less.soluble.than.the.wild-type.protein,.which.
explains.its.higher.propensity.for.aggregation.into.insoluble.aggregates.as.compared.
to.the.wild-type..If.the.mutant.is.already.less.soluble.than.the.wild-type,.any.changes.
in.the.environment.of.the.cell.could.further.decrease.its.solubility.and.thus.increase.
its. rate. of. aggregation.. Small. changes. in. the. intracellular. environment. can. have. a.
signiicant.impact.on.the.intracellular.components.
The. thermodynamics. characteristics. of. the. synuclein. variants,. which. have. not.
been. investigated. previously,. have. also. been. calculated. in. our. studies.. While. the.
deviation.of.the.average.Gibbs.free.energy.of.the.proteins.during.these.simulations.
does.not.allow.for.a.direct.comparison,.the.general.trend.of.the.data.can.be.taken.
into.account..The.most.signiicant.contribution.to.the.average.free.energy.of.each.of.
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