concentration of electronegative atoms on the major groove side and electropositive atoms on the minor
groove side. The dipole of an asparagine or glutamine side chain can match the local dipole of the nucleotide
(Figure 10.4e). Dipoles also affect the stacking of the bases in G/C rich sequences. To a first approxima-
tion, the G C base pair has a large dipole along its long axis resulting from the cluster of partial negative
charge on the G and partial positive charge on the C. Dipoles align to maximize attraction and minimize
repulsion, and it can be envisaged how the sandwiched G C dipoles in a sequence like GGGG/CCCC
favour high slide, whilst low slide is preferred for an alternating sequence such as GCGC/CGCG. In con-
trast, the A T base pair contains only small patches of isolated positive and negative electrical charge along
its long axis, which are relatively dispersed over the entire pair, and therefore do not amount to a sub-
stantial dipole.
Stacking interactions can also occur between aromatic residues in a protein and unstacked bases, for
example in the intercalation of a Phe side chain between two unstacked nucleotides (Figure 10.4f).
10.3 Representative DNA Recognition Motifs
10.3.1 The Tree of Life and its Fruitful Proteins
Protein folds that are used in recognition of DNA (and RNA) may be grouped according to their structural
and evolutionary relationships. But before grouping such folds into classes, it is useful to be aware of how
organisms are grouped. All cellular life on Earth can be organized into three domains: the eukaryotes, the
bacteria and the archaea. Eukaryotes and archaebacteria may have shared a common ancestor during a
period of evolutionary history following the divergence from bacteria.^9 During the subsequent evolution
of the archaea, there was a split into the sub-domains known as the crenarchaeotaand the euryarchaeota.
While eukaryotes and bacteria have many distinguishing features, the archaea share certain molecular simi-
larities with both these groups. For instance, the DNA of eukaryotes is packed tightly into cellular nuclei,
while bacteria and archaea both lack nuclei. On the other hand, the archaea control the expression of their
genes by mechanisms that are more similar to those of the eukaryotes, and they use similar proteins in the
initiation of transcription. In all three taxonomic domains, the core of the RNA polymerase is conserved
in structure and function (Section 10.7.2). The packaging of DNA is important for all cells (Sections 6.4
and 10.6), and the euryarchaecontain histone proteins that are similar to those that compact DNA in the
nuclei of eukaryotes. In contrast, the crenarchaelack histones but have two DNA-binding proteins that
compact relaxed or supercoiled DNA.^10
In all organisms, gene expression is highly coordinated and regulated. In bacteria and archaea, related
genes are clustered together in the genome, and a single DNA-binding protein is often used to control the
transcription of individual clusters (Section 6.1). Representative examples in bacteria are the lac, met and trp
repressors. By contrast, in the eukaryotes several ‘transcription factors’ may act together in different com-
binations, so that specificity for individual genes is achieved through protein–protein interactions. Another
distinguishing aspect of eukaryotic genes is that their activities are generally repressed by chromatin struc-
ture. Thus, covalent modification of histones by acetylation and methylation plays an important role in gene
expression by affecting the access of the chromatin to transcription factors.
DNA-binding domains in proteins from all of these taxonomic domains of life can be classified into the
order of dozens of distinct groups according to recurring structural motifs. The structural element employed
most frequently is the -helix. Less frequently found are -ribbons, -sheetsand loops. The major
groove of DNA is most often the target for recognition. But in some cases recognition is mediated by bind-
ing in the minor groove. An example of this is the DNA complex of the TATA-binding protein (TBP)
(Section 6.6.3). Some of the motifs are very ancient and can be found in archaea, bacteria and eukaryotes
alike. Others are clearly more recent, for instance the homeodomain transcription factor which occurs only
in higher eukaryotes (Figure 10.2a). Here, we describe a representative selection of these various folds.
Interactive websites provide more details of many of the known motifs (http://www.biochem.ucl.ac.uk/
bsm/protdna/prot dna_cover.html).
Protein–Nucleic Acid Interactions 391