First Principles DFT Studies of Metal-Based Biological and Biomimetic Systems - Metallic Systems: A Quantum Chemist's Perspective - page 13

The.NMR.structure.of.the. 1 -DNA.complex.has.been.used.as.a.template.to.construct.
models.of. 2 -DNA.adducts,.considering.both.the.N1,N2.and.the.N1,N3.binding.modes.
( B .and. C ,.respectively).for.which.no.structural.information.was.available. 68
The. overall. agreement. between. the. average. QM/MM. structure. of. A . and. the.
NMR.structure.validates.our.computational.setup..As.a.general.feature,.the.drug-
DNA.complexes. A .and. B .display.almost.the.same.structural.properties,.whereas.a.
slightly.different.structure.is.observed.for. C ,.due.to.its.larger.intermetal.distance. 68
As.displayed.in.Table.1.2,.the.binding.of.the.dinuclear.drugs.is.characterized.by:.
(i). a. decrease. in. the. roll. angle. of. the. platinated. G5-G6. bases. when. going. from. A .
to. C ,. which. in. C . becomes. negative. and. markedly. smaller. than. in. cisplatin-DNA.
adducts,. (ii). an. increase. of. the. rise. at. the. platinated. G5-G6. base. step. that. in. C .
becomes. comparable. to. the. one. observed. in. cisplatin-DNA. adducts,. (iii). a. wider.
major.groove.with.respect.to.canonical.B-DNA,.and.(iv).a.small.overall.axis.bend.
for.all.three.complexes. 68 .Interestingly,.cisplatin.causes.exactly.the.opposite.effects.
on.the.helical.parameters. 67
Although.our.results.do.provide.a.detailed.picture.of.local.distortions.at.the.plati-
nated.site.and.give.some.qualitative.trends.for.the.global.distortions.in.DNA,.the.con-
vergence.of.these.parameters.is.hampered.by.the.ps.simulation.time-scale.accessible.
in.QM/MM.simulations. 66 .To.conirm.the.trend.observed.in.global.DNA.parameters,.
accurate.force.ield.parameters.were.developed.for.the.diplatinum.moiety.embedded.
in.its.biomolecular.environment..This.was.done.using.the.recently.proposed.force-
matching. approach. of. classical. forces. to. ab. initio. forces. extracted. from. QM/MM.
trajectories. 150,151 .This.approach.has.an.advantage.compared.to.conventional.param-
eterization.methods.in.that.the.exact.local.structural.properties.of.the.DNA.duplex.at.
the.drug-binding.site.need.not.be.known.a.priori.since.the.QM/MM.method.can.pre-
dict.small.structural.changes.occurring.upon.DNA.binding..Furthermore,.tempera-
ture.effects.and.the.inluence.of.the.DNA.environment.are.automatically.taken.into.
account. 150 .The.accuracy.of.the.newly.developed.force.ield.parameters.is.validated.
by.comparison.of.structural.properties.from.classical.MD.and.hybrid.QM/MM.sim-
ulations. 151 .The.structural.characteristics.of.the.Pt-lesion.are.well.reproduced.during.
classical.MD.compared.with.QM/MM.simulations.and.available.experimental.data.
(Table.1.2). 151
These.simulations.conirmed.that.upon.binding.the.DNA.duplex.undergoes.minor.
global. distortions.. Interestingly,. the. analysis. of. local. and. global. DNA. parameters.
revealed.that. A .and. B .are.almost.identical,.while.the.N2,.N3.isomerization.of.the.Pt2.
coordination.sphere.imposes.different.structural.properties.in. C ..Thus,.these.simu-
lations.show.that.the.azole-bridged.diplatinum.drugs.do.not.provoke.distortions.in.
the.DNA.duplex.(in. A .and. B ),.while.modest.local.and.global.distortions,.which.are.
exactly.opposite.to.the.ones.induced.by.cisplatin,.occur.in. C . 68,151 .This.may.give.a.
irst.rationale.for.the.lack.of.cross-resistance.of.these.drugs.in.cell.lines.resistant.to.
cisplatin.
Local.helical.parameters.as.well.as.overall.curvature.of.dsDNA.have.been.related.
to. protein. recognition. processes, 152,153 . suggesting. that. even. subtle. differences. may.
play.a.role.in.cellular.events.associated.to.the.recognition.of.platinated. DNA 126,152 .
and. be. directly. related. to. observed. differences. in. cytotoxic. activity. 147 . A. detailed.
understanding. of. how. these. structural. differences. in. cisplatin-. and. diplatin-DNA.