Chemistry Reference
In-Depth Information
positions of the protein specifi cally contact bases and shows what residue sizes are
compatible with these positions, resulting in a unique pattern shared by all members
of each family of DNA-binding proteins.
9
DNA recognition codes were also pro-
posed for other families of DNA-binding proteins such as homeodomains,
10
the
EGR (early growth response factor) family of zinc-fi nger transcription factors
11
and
zinc - fi nger proteins
12
However, it was realized that there is no clear one-to-one cor-
respondence between amino acids and bases.
13
Consequently, the rules cannot be
generalized for all DNA-binding proteins. Furthermore, a rules-based approach is
likely to fail in cases where the same pair interacts using a variety of geometries or
a protein recognizes specifi c DNA sequences indirectly, i.e. via water-mediated
contacts, via specifi c sequence-dependent conformational features and/or via
binding - induced distortion of DNA.
13
In many cases, peptides have been combined with a metal centre in order to
increase their thermodynamic stability and DNA-binding affi nity. In this context,
research has followed mainly two directions. The fi rst approach involves coordina-
tion of a metal ion to a peptide ligand forming metal-peptide complexes. The metal
ion may play a structural role imparting structure to an unstructured peptide and/or
conferring nucleolytic activity. Many excellent reviews are available with informa-
tion about the DNA interactions of several types of metal-peptide complexes, such
as metal complexes of small peptides,
14
lanthanide - based metallopeptides,
15
zinc -
fi nger peptides,
16
chemical nuclease-protein conjugates.
17
On the other hand, the
second approach focuses on appending the peptide either to an aromatic ring or
the backbone of another ligand participating in the coordination of a metal ion, thus
forming metal complex-peptide chimeras or conjugates. Parent metal complexes
are molecules with established DNA-binding properties. Tethering the peptide to
such metal complexes is in most cases anticipated to result in sequence-specifi city
upon DNA - binding.
Transition metal complex-peptide conjugates, discussed herein, offer a new
potential in DNA binding and cleavage. They combine the DNA-binding properties
of metal complexes accomplished via electrostatic and/or van der Waals interactions,
or covalent binding with the ability to form specifi c contacts with the DNA bases
provided by the peptide backbone and side chain donor groups. Additionally, an
appropriately designed metal complex may confer its properties to the chimeric
molecule resulting in DNA conformational, chemiluminescent or fl uorescent probes
and chemical nucleases.
12.2
Transition Metal Complex - Peptide Conjugates
It is generally known that proteins often use a signifi cant percentage of their amino
acids to form the nonspecifi c contacts that provide the affi nity to DNA, while they
use an appreciably smaller number of amino acids to make direct contacts with the
base pairs. Based on this concept, when constructing metal complex-peptide conju-
gates, the metal complex provides nonspecifi c affi nity and less steric bulk and com-
plexity than the full DNA binding protein, while the essential recognition site of
the original peptide motif is maintained.
