Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 40

mechanics/molecular. mechanics. (QM/MM). method. 44 . This. method. enables. more.
accurate. studies. of. systems. with. many. atoms,. such. as. the. present. study. of. metal-
containing.biomolecules.in.aqueous.solution,.by.partitioning.the.system.into.a.part.
which.is.treated.using.a.quantum.mechanics.method.and.a.part.that.is.treated.using.a.
molecular.mechanics.method..Typically,.the.chemically.“interesting”.part.of.the.sys-
tem.is.treated.using.quantum.mechanics.methods..In.the.present.example,.we.treat.
the.metal.ion.and.corresponding.amino.acid.residues.with.the.CPMD.method..This.
enables.the.study.of.bond-breaking.and.bond-forming.interactions.(something.that.
is.not.possible.using.molecular.mechanics.methods).and.provides.detailed.electronic.
structure.information.typical.of.ab.initio.and.DFT.methods.along.with.the.dynami-
cal.information..The.rest.of.the.system.is.treated.with.classical.MD.simulations.as.
described.earlier..We.ind.unprecedented.insights.into.the.impact.of.aqueous.solution.
on.the.protein.structure,.conformation,.and.coordination.chemistry.of.Fe 3+ .ions.with.
α-synuclein.and.A53T,.which.are.presented.in.the.following.text.
Other.computational.studies.have.also.been.performed.on.wild-type.and.mutant.
α-synuclein.monomers..However,.many.of.these.studies.were.performed.in.the.pres-
ence.of.sodium.dodecyl.sulfate.(SDS).micelles.or.lipid.bilayers.due.to.the.theorized.
role. of. α-synuclein. in. vesicle. binding. 2 . The. reported. results. of. these. simulations.
heavily.emphasize.the.interaction.of.α-synuclein.with.SDS.micelles.and.lipid.bilay-
ers.and.very.little.information.on.the.impact.of.the.aqueous.solution.on.the.structure.
of.the.protein.is.described.or.determined. 2
Other.classical.MD.simulations.of.the.wild-type.and.mutant.monomers.in.aque-
ous. solution. have. also. been. performed,. but. the. water. model. used. has. not. been.
speciied,.which.raises.questions.about.the.accuracy.of.the.simulation. 3 .These.pre-
vious.studies.also.provide.only.a.minimal.description.of.the.percentage.of.α-.and.
π-helix.content.of.the.monomer.during.the.course.of.the.simulations, 3 .and.attempt.
to.determine.probable.aggregation.sites.using.a.model.with.questionable.accuracy. 45 .
To. date,. a. detailed. analysis. of. the. structural,. dynamical,. intra-. and. intermolecu-
lar.interactions.of.the.protein.(with.and.without.the.presence.of.aqueous.solution),.
hydration. characteristics,. and. thermodynamic. properties. of. the. monomers. is. not.
available.in.the.literature..The.present.analysis.provides.a.detailed.understanding.of.
the.wild-type.and.A53T.mutant.monomers.as.well.as.a.possible.explanation.for.the.
observed.experimental.differences.between.the.two.variants..Additionally,.we.report.
the.coordination.chemistry.between.the.Fe 3+ .ion.and.the.proteins.and.compare.the.
resulting.structures.to.one.another.
2.2 METHODS
Classical.MD.simulations.operate.by.propagating.the.positions.of.a.set.of.nuclei.as.
a.function.of.time.on.a.potential.energy.surface.representing.a.particular.molecular.
system. according. to. Newton's. equations. of. motion. (hence. the. term. “classical”). 46 .
Such. simulations. permit. particles. to. interact. for. a. period. of. time. and. lead. natu-
rally.to.interpretation.of.results.via.statistical.mechanics..One.of.the.justiications.
for. MD. simulations. is. based. on. the. equality. of. the. statistical. ensemble. averages.
and. corresponding. time. averages.. This. is. known. as. the. “ergodic. hypothesis.”. In.
other.words,.the.time.that.an.atom.is.located.in.a.phase.space.of.microstates.with.