Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 60

The value.of. R ee .for.the.equilibrated.structures.in.aqueous.solution.and.in.the.gas.
phase.changes.by.67.6.Å.for.the.wild-type.and.35.9.Å.for.the.A53T.mutant.synucle-
ins..The.value.of. R ee .is.3.Å.greater.in.the.wild-type.than.the.mutant.in.aqueous.solu-
tion.. Overall,. the. differences. in. the. values. of. R ee . between. the. initial. experimental.
structures.and.the.equilibrated.structures.is.smallest.for.the.wild-type.(1.Å)..These.
results.also.demonstrate.the.lexibility.of.the.proteins.in.the.absence.of.solvent.mol-
ecules.and.indicate.that.the.initial.structures.in.aqueous.solution.are.stabilized.via.
the.interactions.of.the.protein.with.the.surrounding.water.molecules..Thus,.the.cal-
culated.values.of. R ee .in.aqueous.solution.are.similar.for.both.proteins.and.relect.the.
similarity.between.the.two.structures.
In. order. to. provide. a. quantitative. description. of. the. intramolecular. hydrogen.
bonds. that. are. inhibited. by. the. presence. of. water,. the. hydrogen. bonding. in. the.
gas-phase. and. aqueous-phase. structures. was. determined. for. both. proteins.. The.
probability. (Z). of. H-bond. formation. in. the. equilibrated. structures. was. calculated.
by. determining. the. number. of. frames. in. which. the. distance. between. potentially.
hydrogen-bonded. atoms. is. less. than. or. equal. to. 3.Å.. The. potential. of. mean. force.
(PMF).values.(Tables.2.5.and.2.6).were.calculated.as.described.in.Section.2.2..The.
differences.in.the.hydrogen.bonding.highlight.the.differences.in.the.dehydrated.(gas.
phase).and.solvated.structures.
The. most. common. residues. involved. in. hydrogen. bonding. for. the. wild-type.
α-synuclein. protein. are. the. lysine. and. glutamate. amino. acids.. Hydrogen. bonds. to.
these.two.amino.acids.are.also.among.the.most.preferred.in.the.gas.phase.(Table.2.5)..
The.majority.of.the.most.stable.intramolecular.hydrogen.bonds.are.located.between.
the.α-helical.sections.of.the.protein.(residues.3-37.and.45-92).and.the.C-terminal.
tail.(residues.97-140),.explaining.the.structure.of.the.compactly.folded.protein.in.the.
gas.phase..Although.there.are.also.a.number.of.lysine.and.glutamate.intramolecu-
lar. hydrogen-bonds. present. in. aqueous. solution,. the. only. common. intramolecular.
hydrogen-bond. is. the. one. that. is. formed. between. residues. 102. and. 105,. and. even.
so.it.is.not.the.most.preferred.of.all.the.intramolecular.hydrogen-bonds.in.aqueous.
solution.(see.Table.2.5)..These.results.indicate.that.intermolecular.hydrogen.bond-
ing. interactions. with. surrounding. water. molecules. stabilize. the. protein. in. a. rela-
tively.unfolded.conformation.and.prevent.the.formation.of.the.same.intramolecular.
.hydrogen-bonds.that.resulted.in.the.highly.folded.structure.observed.in.the.gas.phase..
Threonine. residues. present. in. the. protein. form. intramolecular. hydrogen. bonds. in.
aqueous.solution.that.are.not.present.in.the.gas.phase.and.highly.preferred.compared.
to. the. other. intramolecular. hydrogen-bonds. of. the. protein. in. solution.. Looking. at.
these. hydrogen-bonds. speciically,. a. pattern. may. be. seen.. All. of. the. bonds. occur.
between.the.hydroxyl.hydrogen.and.a.backbone.carboxyl.oxygen.separated.by.three.
residues.in.the.α-helical.sections.of.the.protein.and,.therefore,.assist.in.stabilizing.
the. observed. α-helical. structure.. Only. between. residues. 68. and. 71. is. a. deviation.
from.the.α-helical.conformation.observed..This.may.be.due.to.lack.of.a.stabilizing.
threonine.intramolecular.hydrogen.bond.within.the.backbone.in.this.region.
The.intramolecular.hydrogen.bonds.and.corresponding.PMF.values.for.the.A53T.
mutant. protein. in. the. gas-phase. and. aqueous. solution. are. presented. in. Table. 2.6..
As. seen. in. the. wild-type. α-synuclein. gas-phase. structure,. the. most. common. and.