Chemistry Reference
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adducts.affect.protein.recognition.and.other.cellular.processes.is.a.highly.challenging.
task. 126
Groove.lexibility.plays.an.important.role.in.many.biological.functions.involving.
DNA;.in.particular,.groove.deformability.can.inluence.DNA.recognition.by.many.
DNA-binding. proteins,. including. those. proteins. involved. in. repair. mechanisms. 152 .
Generally,.the.binding.of.proteins.to.the.DNA.minor.groove.resulted.in.a.signiicant.
deformation.from.the.standard.B-DNA.conformation,.e.g.,.an.opening.of.the.minor.
groove.and.a.bending.of.DNA.toward.the.major.groove. 153,154 .To.date.this.aspect.has.
not.been.considered.in.the.case.of.Pt.drugs,.therefore.we.have.investigated.the.effect.
of.cisplatin.and.dinuclear.Pt.drugs.on.minor.groove.lexibility.by.performing.clas-
sical.MD.simulations.in.combination.with.an.adaptive.bias.force.(ABF) 155 .method.
to.calculate.free-energy.proiles..Simulations.were.carried.out.on. A ,. B ,. C .and.cis-
platin-DNA. ( D ). considering. a. hexadecamer. with. the. same. sequence. as. the. x-ray.
structure.of.the.platined.DNA.in.complex.with.HMG.with.the.sequence.(5′-d(CpCp
UpCpTpCpTpG*pG*pACpCpTpTpCpCp)-3′)..The.free.oligonucleotide.( E ).was.also.
considered.for.comparison. 126
By.choosing.the.reaction.coordinate.as.the.distance.between.the.center.of.mass.
of.the.backbone.atoms.of.G9.and.A10.on.the.irst.strand.and.to.C25.and.A26.on.the.
second.strand.(Figures.1.4.and.1.5),.the.calculated.free-energy.proiles.reveal.that.
G5
Pt
G6
Pt
G7
Pt
G6
Pt
G5
Pt
G6
FIGURE  1.4  (See  color  insert.)  Cisplatin-DNA. adduct. and. (in. the. orange. rectangle). a.
close.view.of.the.cisplatin.binding.region;.yellow.lines.highlight.the.kink.induced.by.cisPt..
Diplatin-DNA.adduct.and.(in.the.blue.rectangle).a.close.view.of.the.N1,.N2.and.N1,.N3.bind-
ing.mode.in. B .and. C .complexes.
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