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within.approximately. 1.ns. and. then. the. structure. does. not. change. signiicantly. for.
the.remainder.of.the.simulation.(19.ns).
In.contrast.to.wild-type.α-synuclein,.our.structural.analysis.reveals.that.the.A53T.
mutant.geometry.in.the.gas.phase.is.completely.different.from.the.wild-type.geom-
etry.in.the.gas.phase..The.initial.and.the.equilibrated.structures.of.A53T.are.more.
similar. than. in. the. case. of. the. wild-type. (see. Figure. 2.2a).. Unlike. the. wild-type,.
the. initial. 92. residues. of. the. A53T. mutant. remain. in. the. α-helical. conformation.
throughout.the.simulation.(see.Figure.2.2b)..Additionally,.the.coil/turn.connection.
between.the.two.α-helical.portions.remains.between.residues.37.and.45.throughout.
the.course.of.the.simulation..While.the.actual.number.of.amino.acids.involved.in.this.
connection.does.not.change,.the.angle.at.which.this.connection.occurs.is.obviously.
different..Also,.there.does.not.appear.to.be.any.additional.unraveling.of.the.α-helical.
conformation.like.what.is.observed.in.the.wild-type.simulation..There.are.similar.
structural.motifs.to.the.changes.in.the.structure.of.the.A53T.mutant.when.compared.
to. wild-type.. There. is. interaction. between. the. N-terminus. and. the. other. α-helical.
portion. of. the. protein. (around. residue. 69). that. is. similar. to. the. interaction. of. the.
N-terminus. in. the. wild-type. structure.. Also,. the. C-terminal. tail. coils. upon. itself.
in.a.similar.manner.to.the.wild-type.structure.except.that.the.remaining.loose.tail.
region.is.approximately.10.residues.long.instead.of.20.residues.long.in.the.wild-type.
structure..The.A53T.mutant.structure.equilibrates.in.about.the.irst.nanosecond.of.
the.simulation.and.the.structure.remains.very.stable.throughout.the.remaining.19.ns..
Thus.the.effect.of.changing.a.single.amino.acid.is.seen.to.have.a.signiicant.impact.
on.the.structural.conformation.of.the.protein.
The. presence. of. an. aqueous. solution. environment. can. also. have. a. signiicant.
impact.on.the.structure.of.a.protein.due.to.various.solute-solvent.interactions,.includ-
ing.the.intermolecular.hydrogen.bonds.formed.between.the.solute.and.solvent.mol-
ecules..The.initial.structures.of.the.wild-type.and.mutant.A53T.were.also.simulated.
in.aqueous.solution.using.an.explicit.model.for.water.as.described.in.Section.2.2.to.
determine.the.differences,.if.any,.between.the.structures. in.the.presence. of.water..
The.results.of.the.simulations.in.the.presence.of.explicit.solvent.molecules.show.that.
the.presence.of.water.does.have.a.signiicant.effect.on.the.structure..The.structures.
of.both.the.wild-type.and.mutant.A53T.α-synuclein.have.greatly.different.confor-
mations. when. compared. to. the. gas-phase. structures. as. well. as. when. the. solvated.
structures.of.each.protein.are.compared.to.each.other.
The.solvated.wild-type.α-synuclein.structure.shows.the.largest.structural.changes.
between.the.initial.experimental.structure.in.the.gas.phase.and.in.aqueous.solution..
The. solvated. structure. resembles. the. initial. experimental. structure. more. than. the.
structures.obtained.from.our.MD.simulations.in.the.gas.phase.(Figure.2.3a)..Again,.
the.changes.in.protein.structure.are.more.easily.observed.by.looking.at.the.second-
ary.structures.throughout.the.course.of.the.simulation,.as.illustrated.in.Figure.2.3b..
Although. the. overall. change. in. structure. is. not. as. signiicant. as. in. the. gas. phase,.
there. are. still. regions. of. the. protein. that. show. signiicant. changes.. In. agreement.
with.the.gas-phase.simulations,.we.observe.that.the.coil/turn.connection.is.between.
residues.37.and.45..However,.this.region.of.the.protein.appears.to.change.its.struc-
tural.characteristics.frequently.throughout.the.course.of.the.simulation..Structural.
changes.between.amino.acids.68.and.71.in.the.middle.of.the.C-terminal.side.of.the.
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