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described by Tanaka
et al.
and it involves the substitution of nucleobase pairs with ligands
that have a high affinity for metal ions [8]. Ligands juxtaposed at complementary posi-
tions within a nucleic acid duplex form a high affinity binding site for metal ions. The
DNA monomers in which the nucleobase was replaced with a ligand were termed ligan-
dosides by Tor
et al.
[11].
This novel class of metal-DNA hybrid structures is interesting for several reasons.
First, it adds a novel dimension to the growing field of artificial base pairs, which were
previously based on alternative hydrogen bonding patterns or on hydrophobic interactions
[39]. The higher strength of coordinative bonds when compared to hydrogen bonds bodes
well for the formation of alternative base pairs whose stability surpasses that of the natu-
ral, Watson-Crick base pairs and may be of interest for applications in nano- or bio-
technology. Second, metal-based alternative base pairs could be used in the extension of
the genetic code [10]. Recent work showed that indeed, metal-containing alternative base
pairs can be recognized and extended by polymerases [15i,40]. Third, for the inorganic
chemist, the interest in such structures is related to the possibility of using the nucleic
acid duplex as a scaffold in which one or multiple metal ions are incorporated in a rational
and controlled manner. The bridging of the gap between extended metal clusters produced
by materials science, and the metal clusters synthesized by supramolecular inorganic
chemistry, makes the efforts aimed at using nucleic acids as scaffold for transition metal
ions worthwhile.
10.3.1 Design Strategy
To make possible metal ion incorporation at specific locations in nucleic acid duplexes,
ligands are included in nucleic acid oligomers, typically in complementary positions.
Most ligands used to date to form metal-ligand alternative base pairs contain aromatic
rings, and can participate in p-p stacking interactions with adjacent bases. Generally
these ligands cannot form hydrogen bonds to bridge the two complementary oligonucleo-
tides forming the duplex. In all studies published so far (most of which are cited in this
and other chapters of this topic), the stability of the ligand-modified duplexes was similar
to or lower than that of the duplexes that have an A
TorG
C base pair instead of the pair
of ligands.
The ligands chosen to create metal-containing nucleic acid duplexes form typically
square-planar metal complexes, can participate in p-stacking interactions (with the adja-
cent base pairs), and have been placed usually in complementary positions within nucleic
acid duplexes. Most of the ligands have 1-3 metal binding sites that are part of aromatic
rings. To ensure that the metal ions are incorporated only at the positions where the
duplex has been modified, the affinity of the ligands for the metal ions must be higher
than that of the natural nucleobases, in particular that of the G bases, which coordinate to
metal ions in a monodentate fashion through GN7. Preferably the metal ions should have
the ability to form square-planar complexes; octahedral complexes with the ligands in
equatorial positions and the axial positions occupied by donor atoms from the adjacent
nucleobases or solvent molecules may also play the role of alternative base pairs.
An important condition that artificial base pairs must fulfill to be useful for the exten-
sion of the genetic code is to be orthogonal to natural base pairs. Therefore, the metal ion
should form complexes only with the extraneous ligands and not mixed-ligand complexes
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