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H
3
N
NH
3
H
3
N
G
Pt
CI
DNA
CI
1-DNA
Pt
G
1
H
3
N
2+
2+
N
3
H
3
N
N
2
-N
1
NH
3
NH
3
Pt
Pt
H
3
N
H
3
N
NH
3
N
2
-N
1
H
Pt
H
3
N
Pt
O
H
NH
3
2
3
NH
3
H
3
N
NH
3
NH
3
Pt1
Pt1
G
G
N
1
N
2
DNA
DNA
N
2
G
N
3
G
N
3
Pt2
Pt2
H
3
N
NH
3
H
3
N
NH
3
B: 3-DNA
C: 3'-DNA
FIGURE 1.3
Cisplatin.(
1
).and.its.adduct.with.dsDNA.(
1
-DNA)..The.azole-bridged.diplati-
num.compounds.[Pt2(
í
-OH)(
í
-pz)]
2+
.(
2
),.[Pt2(
í
-OH)(
í
-1,2,3ta)]
2+
.(
3
),.and.the.atom.numbering.
in.the.rings..Two.different.binding.modes.of.
3
.to.DNA.yield.to.adducts.
B
.and.
C
..The.
2
-DNA.
adduct.(
A
).is.equivalent.to.
B
..(Reprinted.with.permission.from.Katrin.Spiegel.et.al.,.
J. Phys.
Chem. B
,.111(41),.11873..Copyright.Oct.2007.American.Chemical.Society.)
have. been. designed. to. bind. DNA. has. led. to. a. reduction. in. the. structural. distor-
tions.induced.by.cisplatin,.possibly.reducing.the.risk.of.cross.and.intrinsic.resis-
tance.
133,145-147
.Three.hybrid.QM/MM.simulations.(in.which.the.Pt.moiety.and.the.
guanine.are.treated.at.the.QM.level,.while.the.rest.is.treated.at.the.MM.level).were.
performed:.(i).starting.from.the.x-ray.structures.of.platinated.DNA,
142
.(ii).the.cis-
platin-DNA.adduct.in.complex.with.High.Mobility.Group.(HMG).protein,
144
.and.
(iii).from.cisplatin.docked.to.the.same.oligomer.in.the.canonical.B-DNA.confor-
mation.
67
.All.simulations.reproduced.the.relevant.experimental.and.structural.fea-
tures.with.good.accuracy,.even.though.the.DNA.duplex.is.rather.lexible.in.all.three.
models..During.the.simulation,.the.helical.parameters.asymptotically.approached.
the.values.of.the.simulation.based.on.the.x-ray.structure.with.the.rise.increasing.
from.4.to.7.Å,.the.roll.angle.ranging.from.28°.to.61°.and.the.global.axis.curva-
ture.ranging.from.48°.to.57°.
67
.However,.a.complete.structural.agreement.among.
the.three.simulations.is.prevented.by.the.puckering.of.the.sugars:.conformational.
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