Already during my studies of General Chemistry at the University of Basel I became
interested in the chemistry of nucleobases. After studying the acid-base properties
of the widely used nucleotide analog adenosine 5'-O
-thiomonophosphate, additional potentiometric
pH titrations were performed to investigate the metal ion binding properties
of this interesting ligand.
After an excurse to the synthesis of 3-Phenyl-1H
-4-chinolon derivatives as potential
inhibitors of tyrosine kinase, I returned to Bioinorganic Chemistry to investigate the interactions of nucleobases
with metal ions, but now concentrating on platinum(II). A large variety of so-called metal-modified
base pairs was synthesized and subsequently characterized by NMR and/or X-ray crystallography to
gain new insights in the effects of Pt(II) coordination on the properties of nucleobases.
Recently, I switched fields towards "Biochemistry", still having in mind what I did before; in a way just
the size of the molecules was increased. Now, I am working with catalytic RNAs, i.e. ribozymes, and I try
to localize the metal-ion binding sites in group II intron ribozymes.
The main interest of my Ph.D. thesis in the group of Prof. Dr. Bernhard Lippert
on the effect of metal ion binding to nucleobases with regard to their hydrogen bonding properties. As Cisplatin
and its derivatives are widely used anticancer drugs, the target being DNA, Pt(II) complexes of nucleobases were synthesized.
Concentration dependent NMR measurements
with several Pt(II)-nucleobase complexes revealed that Pt(II) coordination to N7 of a guanine nucleobase
increases the strength of the hydrogen bonds
in its Watson-Crick base pair with cytosine. These studies included the synthesis of platinated nucleobase quartets
and they also led to the
characterization of a CH--N hydrogen bond
in a platinated nucleobase quartet and a to hitherto unknown hydrogen bonding pattern between guanine and cytosine.
Most of these compounds could be analyzed in solution as well as in the solid state.
In an additional project, platinum(II) entities were used as linkers between nucleobases and first examples of synthetic
cationic oligonucleotide derivatives were constructed.
Group II intron ribozymes are the largest known catalytic RNAs and consist of more than 1000 nucleotides.
One member of this family, the ai5gamma intron, is in the center of interest in the ongoing research
in the group of Prof. Dr. Anna Marie Pyle
, with the aim to reveal the structure
and the multiple functions of this class of ribozymes. We are only at the beginning of getting a first image
of the three-dimensional structure of this macromolecule.
My research focuses on the localization of metal ions within the tightly packed domains of ai5gamma.
The general idea is that many of these metal ions are simply required for charge compensation of the negatively charged phosphate-sugar
backbone and that they are only unspecifically bound. But a minority is bound specifically and is of structural importance,
i.e. by stabilizing a kink in the backbone or a tertiary interaction of two helices. Others even participate in
the chemical reactions of the RNA molecule.
Recently, we identified several metal ion binding sites in ai5gamma by Terbium(III) mediated hydrolysis
of the phosphate-sugar backbone. Since this method only reveals those binding sites, where the metal ion
is located in the minor groove, we are now trying to locate also the major-groove bound ions, and
to gain more specific information of the actual binding mode of the ions.