First Principles DFT Studies of Metal-Based Biological and Biomimetic Systems - Metallic Systems: A Quantum Chemist's Perspective - page 12

TABLE 1.2
Selected Helical Parameters at the N7(G)-N7(G) Crosslink Formed by
Pt-Drugs Binding to DNA: [Pt 2 (μOH)( ~ -pz)](NO 3 ) 2 (pz = Pyrazolate) (1) and
[{ cis -Pt(NH 3 ) 2 } 2 (μ-OH)(μ-1,2,3-ta-N1,N2)](NO 3 ) 2 (ta = 1,2,3 Triazolate) (2)
Bound to 5 ′ -d(CpTpCpTpG*pG*pTpCpTpCp)-3 ′ , Resulting in Complexes A, B,
and C (Figure 1.3), Compared to NMR structure, 149 and Reference
Simulation of the Unbound Decamer with the Same Sequence (DNA MD)

A B C A B C

QM/MM QM/MM QM/MM CMD CMD CMD DNA MD NMR

Rise 3.6.±.0.2 3.6.±.0.2 4.1.±.0.3 3.5 ± 0.3 3.4 ± 0.3 4.1 ± 0.5 3.4 ± 0.2 3.3

Roll 9 ± 4 4 ± 4 −5 ± 5 6 ± 7 6 ± 5 −14 ± 9 −3 ± 7 5

Global.axis.
curvature

19 ± 5 10 ± 3 8 ± 4 18 ± 9 18 ± 3 14 ± 7 19 ± 8 5

Rise,.major.and.minor.groove.width.(W).and.depth.(D).are.given.in.[Å],.Roll.and.global.axis.curvature.
are.in.degrees..The.minor.and.major.groove.parameters.refer.to.the.largest.value.measured.at.the.plati-
nated.site.(G-G.step)..Structural.parameters.resulting.from.QM/MM.MD.and.classical.MD.are.labeled.
as.QM/MM.and.CMD,.respectively.

changes. of. the. sugar. occur. on. a. time. scale. of. hundreds. of. ps. and. thus. are. not.
accessible. on. our. simulation. time. scale.. Nevertheless,. the. extent. to. which. DNA.
can.rearrange.in.a.few.ps.suggests.that.our.method.may.qualitatively.predict.struc-
tural. changes. of. drug-DNA. adducts. for. which. limited. structural. information. is.
available.
Azole-bridged. dinuclear. platinum(II). compounds. ( 2 ,. 3 ,. Figure. 1.3) 146,147 . have.
been.speciically.designed.to.bind.DNA,.inducing.small.structural.changes.in.order.
to.render.the.platinated.lesion.less.recognizable.by.repair.enzymes. 133 .This.hypothe-
sis.was.conirmed.by.the.NMR-structure.of.the. 2 -DNA.(the.only.available.structural.
information. of. a. diplatinated. drug-DNA. complex). showing. structural. parameters.
very. similar. to. that. of. canonical. B-DNA. (Table. 1.2) 133,148,149 . and. by. an. improved.
cytotoxic.behavior.of.these.drugs.an.relative.to.cisplatin.in.several.tumor.cisplatin.
resistant.cell.lines. 147
Experiments.show.that.for. 3 ,.the.mechanism.of.binding.to.dsDNA.is.quite.com-
plex. 147 .For.instance,.after.the.irst.alkylation.step,.a.nucleophilic.attack.of.the.second.
guanine. can. occur. or,. alternatively,. Pt2. (and. its. coordination. sphere). can. migrate.
from.N2.to.N3,.followed.by.the.second.alkylation.step..Therefore,. 3 .can.alkylate.two.
adjacent.guanines.of.dsDNA.in.both.an.N1,N2.and.an.N1,N3.mode..The.N1,N3.iso-
mer.presents.a.larger.intermetal.distance.and.can.lead.to.the.formation.of.a.variety.of.
inter-.and.intrastrand.crosslinks.which.may.be.a.key.factor.for.the.high.cytotoxicity.
of.these.drugs. 147
Since.the.QM/MM.approach.has.been.of.help.in.characterizing.the.structural.prop-
erties.of.the.cisplatin-DNA.adduct 67 .we.have.also.used.it.to.characterize.and.predict.
the.structural.features.of. 2 .and. 3 .in.complex.with.the.dsDNA.decamer.( A - C ). 66,68 .