Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 39

computational.techniques.could,.however,.provide.strong.evidence.as.to.the.validity.
of.the.early.aggregation.and.monomer.hypothesis. 39
Many.theories.as.to.etiology.of.Parkinson's.disease.have.been.proposed,.but.as.
explained.throughout.the.preceding.paragraphs,.the.mechanisms.by.which.these.the-
oretical. processes. progress. remain. mostly. unexplored.. Current. experimental. tech-
niques. cannot. measure. at. the. molecular. level. and. therefore. the. mechanistic. detail.
from. experimental. data. is. minimal.. However,. a. true. understanding. of. the. mech-
anism. through. which. Parkinson's. disease. progresses. can. only. be. gained. through.
understanding.reaction.mechanisms.at.a.molecular.level..Since.experiments.cannot.
currently.measure.reactivity.at.this.level,.the.most.effective.means.of.determining.
this.mechanism.is.through.computational.studies.
Through. molecular. dynamics. (MD). simulations. of. α-synuclein. and. other. fac-
tors. believed. to. affect. α-synuclein,. such. as. phosphorylation,. oxidative. modiica-
tion,.and.metal.binding,.a.clearer.understanding.of.the.path.leading.to.α-synuclein.
conformational.changes,.aggregation,.and.toxicity.can.be.reached..MD.simulations.
provide.insight.into.intra-.and.intermolecular.hydrogen.bonding,.torsion.transitions,.
solvation.effects,.and.thermodynamic.properties..The.results.from.these.simulations.
can. be. compared. to. experimental. data. to. conirm. that. the. theoretical. studies. are.
in. agreement. with. experimental. indings.. Experimental. techniques. are. especially.
deicient. in. gaining. information. about. the. local. molecular. structure. of. the. solvent.
around.the.protein.and.the.impact.of.the.solvent.on.the.protein.structure..Knowledge.
at.this.level.can.only.be.gained.through.MD.simulations.
Theoretical.studies.have.been.extremely.useful.in.investigations.of.the.structural.
and. conformational. properties. of. biomolecules. in. solution.. Classical. MD. simula-
tions.have.been.applied.extensively.in.these.studies. 42,43 .Even.though.these.simula-
tions.ignore.quantum.effects.and.many.body.interactions.(usually.higher.than.three.
body.terms).and.depend.strongly.on.the.quality.of.the.force.ield.parameters,.results.
obtained.for.proteins.and.peptides.using.these.tools.are.largely.in.agreement.with.
existing. experimental. data.. In. addition,. ab. initio. electronic. structure. calculations.
have.been.performed.on.biomolecules.in.solution,.but.they.cannot.capture.dynamic.
changes.in.the.intermolecular.hydrogen.bonds.or.study.large.size.biomolecules.
Besides.ab.initio.electronic.structure.calculations,.ab.initio.MD.simulations.using.
the.Born-Oppenheimer.or.Car-Parrinello.approaches.study.aqueous.biomolecules.
using. dynamics. based. on. traditional. ab. initio. (Hartree-Fock. based). and. density.
functional. theory. (DFT). calculations. of. the. potential. energy. surface,. respectively,.
and.thus.capture.both.the.impact.of.dynamical.changes.in.intermolecular.hydrogen.
bonding.interactions.and.of.the.dynamics..Even.though.these.ab.initio.simulations.
are. more. accurate. and. powerful,. the. practical. size. of. the. system. currently. cannot.
exceed.200.atoms.
Here,. we. illustrate. the. importance. of. the. inclusion. of. solvent. effects. via. com-
parison. of. the. structures. and. conformations. of. α-synuclein. and. A53T. obtained.
from.gas.and.aqueous-phase.simulations.as.well.as.investigate.metal.ion.coordina-
tion. effects.. The. protein. structure. and. conformation. studies. have. been. performed.
using.classical.MD.simulations.as.described.earlier.and.the.coordination.chemistry.
studies.of.α-synuclein.and.A53T.with.Fe 3+ .ions.have.been.performed.using.CPMD/
MM.simulations..The.CPMD/MM.simulations.are.an.example.of.a.mixed.quantum.