Sequence - Selective Binding of Transition Metal Complexes to DNA - Metal Complex-DNA Interactions - page 5

factors exists, and has been used to predict which DNA site is the most reactive to
metalation or methylation.
In this chapter we present data on sequence-selective interactions between
metal complexes and nucleic acids. In the outline we will distinguish between (i)
site-selective inner-sphere metal coordination of nucleobases, and (ii) the selectivity
of fully hydrated species located in the minor or major groove through hydrogen
bonding and electrostatic interaction. In the former case a further distinction will
be made between labile and nonlabile metals.

1.2 Ab initio Calculations and Photo- Cleavage Studies

The highest occupied molecular orbital (HOMO) of DNA nucleobases plays a
crucial role in metal coordination by interacting with the lowest unoccupied molecu-
lar orbital (LUMO) of metal ions. 15 The calculations of HOMOs of macromolecules
such as duplex DNA are extremely diffi cult. Consequently, there has been little
focus on the role of the HOMO/LUMO in studies of DNA-metal ion interactions.
Theoretical calculations of DNA bases have mostly focused on ionization potentials
(IP) of monomeric nucleobases and the stability of the nucleobase pair in neutral
and radical cation states. 16 About ten years ago the Saito group published the fi rst
extensive studies on the variation of nucleobase IPs and localization of HOMOs as
a function of base stacking, using high-level ab initio calculations. 17 The IPs of four
base monomers and 16 sets of nearest-neighbour stacked nucleobases in the B form
were calculated. It was found that the GG/CC system has the lowest IP among ten
possible stacked nucleobase pairs and that approximately 70% of the HOMO is
localized on the 5 ′ - G of 5 ′ - GG - 3 ′ . These calculations indicate that the 5 ′ - G of 5 ′ - GG -

3 is the most electron-donating site in B-DNA. The origin of IP lowering as a result

of base stacking was further investigated by calculations of HOMO energy distribu-
tion as a function of the twist angle of a GG dimer. 17 Within a normal range of twist
angles for B-DNA (

′

45 °), IP values of GG are between 7.2 and 7.4 eV and
the HOMO is predominantly localized on 5

− 25 ° to −

′ -G. This implies that in B-form DNA

the 5 sequence is the most strongly interacting site with

electrophiles. This principle may be very important in governing sequence-selective
metal binding to DNA.
According to the theoretical calculations, HOMOs of GG sites in duplex DNA
should serve as the most reactive one-electron oxidation sites. In order to verify this
assumption experimentally, Saito et al. performed laser fl ash photolysis of duplex
DNA oligonucleotides with added photosensitizer (photocleaving aminoacid, PCA)
and subsequent hydrolysis dephosphorylation with alkaline phosphatase (Scheme
1.1 ). 18
The G 3 : G 4 ratio (84 : 16) determined by HPLC implies that the major degrada-
tion pathway of the hexamer involves the G 3 site - the most readily oxidizable site
according to theoretical calculations. It should be noted that photo-irradiation of
the single-strand alone results in a nonselective cleavage at G 3 and G 4 in the ratio
1 : 1.

′ -side G of the 5 ′ - GG - 3 ′