Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 57

α-helical.conformation.from.residues.3.to.36.and.45.to.92.making.up.almost.60%.of.
the.protein.structure.completely.disappears.during.the.simulation..The.majority.of.
the.protein.converts.to.a.turn.conformation,.as.shown.by.a.55%.increase.in.content..
Some.of.the.α-helix.and.coil.regions.of.the.protein.are.also.converted.to.a.3 10 -helix,.
which.increases.from.0%.to.11%..The.bridge.β.conformation.between.residues.119.
and.123.disappears.completely.within.1.ns..Four.percent.of.the.protein.briely.con-
verts.to.a.π-helix.conformation.between.residues.69.and.73,.but.this.conformation.
does. not. persist.. In. aqueous. solution,. a. different. trend. is. observed:. approximately.
60%.of.the.protein.remains.in.an.α-helical.conformation.while.24%.is.in.a.coil.struc-
ture.and.14%.is.in.a.turn.structure..The.bridge.β.structure.between.residues.119.and.
124.returns.after.4.ns..Additionally,.a.3 10 -helix.forms.between.residues.98.and.100,.
accounting.for.the.2%.decrease.in.the.degree.of.coil.of.the.protein.
For.the.A53T.mutant.simulated.in.the.gas.phase,.the.α-helix.structure.comprising.
60%.of.the.protein.between.residues.3.and.36.and.45.and.92.remains.fairly.constant.
throughout.the.course.of.the.simulation,.decreasing.by.only.1%..The.degree.of.the.
coil.regions.decreases.by.8%.and.is.converted.along.with.the.bridge.β.conformation.
between.residues.119.and.123.to.a.turn.conformation..In.aqueous.solution,.the.struc-
tural.conformation.remains.constant.except.for.conversion.of.the.bridge.β.conforma-
tion.to.a.coil.conformation.
Even. though. the. secondary. structure. analysis. indicates. that. the. structures. and.
conformations.of.both.the.wild-type.and.mutant.synucleins.remain.similar.to.their.
initial. structures. in. aqueous. solution,. a. more. detailed. comparison. can. be. made.
by. analyzing. the. dihedral. angle. changes. of. the. backbone. atoms. of. these. proteins..
Table.2.3.provides.a.summary.of.the.calculated.dihedral.angles.that.show.signiicant.
changes.during.the.course.of.our.simulations.in.aqueous.solution..In.the.wild-type.
protein,. the. dihedral. angles. that. undergo. the. greatest. change. (between. 100°. and.
150°).occur.in.the.C-terminal.tail.except.for.the.dihedral.angles.from.43N.to.44N,.
which.correlate.to.the.observed.structural.changes..The.remaining.dihedral.angles.
luctuate. between. 70°. and. 90°,. but. also. occur. in. the. C-terminal. tail. except. for.
39N-40N..There.are.also.a.few.dihedrals.(124N-125N,.127αC-128αC,.127N-128N,.
97αC-98αC).that.are.initially.very.lexible.(having.a.large.standard.deviation).and.
end.up.rigid.(having.a.signiicantly.smaller.deviation)..Only.one.bond.exhibits.the.
opposite.trend.(126αC-127αC).
In.the.case.of.the.mutant.protein,.dihedrals.that.undergo.the.greatest.change.are.
also.in.the.C-terminal.tail.except.for.44αC-45αC..The.remaining.dihedral.changes.
also. occur. in. the. C-terminal. tail. except. for. the. 44C-45C. and. 39N-40N. dihedral.
angles..In.addition.to.the.dihedral.angles.listed,.several.regions.of.the.protein.were.
found. in. the. C-terminal. tail,. the. coil/turn. region. from. residues. 37. to. 44. and. the.
region.from.residues.67.to.70.that.are.extremely.lexible.(also.having.large.values.of.
standard.deviation.due.to.their.lexibility).throughout.the.course.of.our.simulation..
These. lexible. regions. and. regions. of. greatest. change. account. for. the. luctuating.
structural. changes. illustrated. in. Figures. 2.1. through. 2.4,. especially. from. residues.
67.to.70.
Perlmutter.et.al..have.also.performed.MD.simulations.of.wild-type.α-synuclein.
as.well.as.the.A53T.mutant,.but.in.the.presence.of.SDS.micelles.and.lipid.bilay-
ers. because. the. protein. is. thought. to. play. a. role. in. synaptic. vesicle. regulation. by.