Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 65

These. studies. show. that. the. aggregation. of. α-synuclein. that. is. .characteristic. of.
Parkinson's. disease. may. be. a. result. of. changes. in. the. hydration. characteristics. of.
the. monomers. 39 . Using. this. technique. in. the. future. may. aid. in. the. experimental.
determination.of.the.mechanism.of.ibrillation.associated.with.Parkinson's.disease..
However,.the.actual.coordination.of.water.molecules.to.the.protein.is.not.revealed.
by.this.technique.
Other.factors.have.also.been.shown.experimentally.to.affect.the.aggregation.of.
synucleins. in. vitro.. Uversky. et. al.. showed. that. by. altering. solution. conditions,. a.
partially. folded. intermediate. is. observed. that. is. thought. to. be. the. middle. ground.
between.the.natively.unfolded.protein.and.the.ibril.aggregates. 31 .Through.further.
experimentation,. they. have. demonstrated. that. several. factors. including. decreased.
pH,. increasing. temperature,. increased. protein. concentration,. and. the. presence. of.
metal.cations.increase.the.rate.of.ibrillation.of.both.the.wild-type.and.A53T.mutant.
synucleins,. where. the. rate. of. ibrillation. in. the. A53T. mutant. is. faster,. perhaps. by.
increasing.the.formation.of.the.partially.folded.intermediate. 31 .While.these.experi-
ments. have. shown. what. conditions. increase. ibrillation,. the. mechanism. through.
which.it.occurs.still.remains.unknown..In.relation.to.our.studies,.perhaps.the.changes.
in.solution.conditions.result.in.a.less-hydrated.protein.that.allows.the.formation.of.an.
intermediate.that.is.similar.to.the.structures.observed.in.our.gas.phase.simulations,.
and.this.leads.to.a.greater.proclivity.for.aggregation..Therefore,.to.fully.understand.
the.mechanism.of.aggregation.in.vivo,.the.effects.of.hydration.must.be.taken.into.
account.
As.part.of.our.studies,.we.have.investigated.the.hydration.characteristics.of.the.
protein..Table.2.7.summarizes.the.coordination.number.of.surrounding.water.mol-
ecules.for.the.most.and.least.hydrated.residues.of.the.wild-type.α-synuclein.in.aque-
ous. solution.. All. other. residues. in. the. simulation. have. intermediate. coordination.
numbers. (varying. between. 2.5. and. 4.5).. This. data. shows. that. the. N-. and. C-helix.
regions.contain.most.of.the.least.hydrated.residues.while.the.majority.of.the.most.
hydrated. residues. reside. in. the. C-terminal. tail.. However,. there. are. a. few. notable.
exceptions.to.this.general.observation..The.glycine.amino.acid.in.position.41.is.one.
of.the.most.hydrated.residues.and.remains.at.approximately.the.same.coordination.
throughout. the. course. of. the. simulation.. This. is. unexpected. considering. its. non-
polar.character..Also,.it.is.unexpected.that.out.of.all.the.polar.residues.in.the.coil/
turn.connection,.the.most.hydrated.is.a.nonpolar.residue..Another.surprising.result.
is. that. the. least. hydrated. residue,. although. nonpolar,. is. the. valine. at. position. 118.
in.the.C-terminal.tail..The.terminal.residues.start.as.the.most.hydrated.residues.of.
the.protein.but.as.the.simulation.progresses,.the.C-terminal.coordination.increases.
and.the.N-terminal.dehydrates.to.an.intermediate.coordination,.which.is.unexpected.
.considering. the. polar. character. of. the. N-terminal. methionine. and. the. nonpolar.
character.of.the.C-terminal.alanine..The.dehydration.at.the.N-terminal.residue.sug-
gests.that.perhaps.the.N-terminal.is.involved.in.the.aggregation.mechanism.of.the.
monomers.
Table. 2.8. summarizes. the. hydration. characteristics. of. the. A53T. mutant.. All. of.
the.other.residues.in.the.simulation.have.intermediate.coordination.numbers.(vary-
ing.between.2.5.and.4.5)..As.in.the.wild-type.protein,.the.N-.and.C-helix.regions.