Chemistry Reference
In-Depth Information
1.4 Summary of Theoretical and Experimental Evidence for
Sequence-Selective Binding to DNA
Paramagnetic and diamagnetic ions are shown to form both labile and nonlabile
adducts with DNA duplexes, and in a series of G-containing duplexes a certain
selectivity pattern emerges where the metal prefers the 5
′
- G in the following
order: 5
′
- GG
>
5
′
- GA
>
5
′
- GT
>>
5
′
-GC. The adjacent residue (Y) on the 5
′
- side
(5
-YGG) is found to exert a negligible infl uence on the selectivity. For the mono-
functional binding of [PtCl(dien)]
+
to double helical DNA the variation in reaction
rates follows qualitatively the same selectivity pattern as for the labile metal ions.
Experimentally observed relative rates of G-oxidation are found to match well with
the NMR results. Nonselective equal G cleavage is observed for single-stranded
DNA, in line with the NMR experimental data.
Ab initio
molecular orbital calcula-
tions of stacked DNA bases with B-form geometry clearly indicated that the highest
occupied molecular orbital (HOMO) localization on the 5
′
- G is highly sequence -
dependent. The degree of p
-
p interaction between the stacked bases infl uences the
HOMO energies. However, it should be emphasized that for metal complexes the
stereochemistry of the ligands also plays a signifi cant role in determining the most
favourable binding site.
′
1.5 Sequence - Specifi c Groove Binding
Among the large number of contributions to the fi eld of cation-groove interaction,
probably a majority is based on X-ray crystallography. Sequence-specifi c nucleic
acid conformation and dynamics are directly infl uenced by metal ions. DNA con-
formational heterogeneity has been explained by an electrostatic model where the
local position and transient fl uctuation of ions act through asymmetric neutraliza-
tion of phosphate charges. Evidence from NMR spectroscopy, X-ray crystallography
and molecular dynamics simulations has revealed that B-form duplexes interact in
a sequence-specifi c manner with fully hydrated mono and divalent cations.
55
1.5.1 Groove Geometry
A noteworthy feature of B-DNA is the presence of two kinds of grooves, called the
major groove (12 Å wide) and the minor groove (6 Å wide) (see fi gures in biochem-
istry text books). They arise because the glycosidic bonds of a base pair are not
diametrically opposite each other. The minor groove contains the pyrimidine O2
and the purine N3 of the base pair, and the major groove is on the opposite side of
the pair. In the minor groove, N3 and O2 can serve as hydrogen bond acceptors,
and the amino group attached to guanine can be a hydrogen donor. In the major
groove N7 is a potential hydrogen bond acceptor, as are O4 of thymine and O6 of
guanine. The amino groups attached to adenine and cytosine, respectively, can serve
as hydrogen donors.
