Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 75

FIGURE 2.7 (See color insert.) Pictorial. representation. of. the. Fe 3+ . ion. coordination. to.
the.His50.residue.of.the.mutant-type.A53T.α-synuclein.protein.in.water.at.room.temperature.
obtained.from.QM/MM.simulations.
2.4 CONCLUSION
Although.the.structural.properties.for.α-synuclein.have.been.determined.experimen-
tally,.the.differences.between.the.dynamical.structure,.hydration.characteristics,.and.
thermodynamic.properties.of.the.two.variants.at.a.molecular.level.had.not.yet.been.
determined..Our.studies.have.revealed.that.there.are.noticeable.dynamic.structural.
differences.between.the.wild-type.and.the.A53T.mutant.both.in.the.gas.phase.and.
in.aqueous.solution.
As. discussed. in. this. chapter,. the. structures. of. both. variants. are. vastly. different.
in.the.gas.phase..Without.the.presence.of.solvent.molecules,.the.protein.structure.is.
altered.from.the.observed.experimental.structures.to.the.structures.shown.in.this.chap-
ter..These.structures.are.extremely.stable.and.the.original.solvated.coniguration.is.not.
regained. on the timescale of the simulation .when.the.molecules.are.again.solvated..
This.result.indicates.that.for.further.experimental.and.theoretical.studies.of.the.aggre-
gation.of.these.proteins,.the.impact.of.the.solution.environment.cannot.be.ignored.
One.of.the.hypotheses.for.the.progression.of.Parkinson's.disease.(as.well.as.other.
neurodegenerative. disorders). is. that. the. brains. of. affected. patients. become. dehy-
drated.compared.to.unaffected.brains..In.the.case.of.a.dehydrated.brain,.the.inhi-
bition. of. the. intramolecular. interactions. by. water. molecules. observed. in. the. fully.
solvated.simulations.would.not.be.as.complete..As.a.result,.the.intramolecular.inter-
actions.may.cause.the.protein.to.fold.into.the.partially.folded.intermediates.that.are.
proposed.to.be.the.intermediate.structure.between.the.free.monomer.and.the.aggre-
gate.state.present.in.Lewy.bodies.and.synuclein.ibrils..In.future.studies,.the.impact.
of.these.interactions.on.aggregation.should.be.investigated.
Not.only.are.differences.evident.between.the.gas.phase.and.aqueous.solution.struc-
tures,.but.the.wild-type.and.A53T.mutant.synucleins.exhibit.structural.and.dynamical.
differences.throughout.the.course.of.the.simulations..The.most.notable.structural.dif-
ference.between.the.two.variants.is.that.the.N-terminus.of.the.A53T.mutant.interacts.
with.the.C-helix.of.the.protein,.which.may.explain.its.increased.rate.of.aggregation.