Tertiary structure
Main article: Nucleic acid tertiary structure
DNA structure and bases
A-B-Z-DNA Side View
The tertiary structure of a nucleic acid is its precise three-dimensional structure, as defined by the
atomic coordinates.[2] RNA and DNA molecules are capable of diverse functions ranging from
molecular recognition to catalysis. Such functions require a precise three-dimensional tertiary
structure. While such structures are diverse and seemingly complex, they are composed of recurring,
easily recognizable tertiary structure motifs that serve as molecular building blocks. Some of the
most common motifs for RNA and DNA tertiary structure are described below, but this information
is based on a limited number of solved structures. Many more tertiary structural motifs will be
revealed as new RNA and DNA molecules are structurally characterized.
Quaternary structure
http://upload.wikimedia.org/wikipedia/commons/thumb/9/
9e/Parallel_telomere_quadruple.png/300pxParallel_telomere_quadruple.png
The quaternary structure of a nucleic acid refers to the interactions between separate
nucleic acid molecules, or between nucleic acid molecules and proteins. The concept is
analogous to protein quaternary structure, but as the analogy is not perfect, the term is used to
refer to a number of different concepts in nucleic acids and is less commonly encountered.
Quaternary structure can refer to the higher-level organization of DNA in chromatin,[1]
including its interactions with histones. It may also refer to the interactions between separate
RNA units in the ribosome[2][3] or spliceosome. The term has also been used to describe the
hierarchical assembly of artificial nucleic acid building blocks used in DNA
nanotechnology.[4]
4.4. H-DNA: THREE’S A CROWD
When a single DNA strand invades the major groove of a DNA duplex, a triple helical structure is
generated (Fig. 9). In order for the duplex to accommodate this third strand, it must unwind to broaden the
major groove; thus, such triple-stranded helices are favored in negatively supercoiled DNA (Mirkin, 2008).
The invading third strand can be intermolecular or intramolecular.
The interaction between strands involve the Hoogsteen edge of the Watson-Crick base pairs (Fig. 3) of the
duplex to form base triplets, leading to the name H-DNA for such triplex structures. H-DNA is formed
primarily in mirror repeat sequences (sequences that have dyad symmetry within a strand, as in
…AGAGGGnnnGGGAGA…, definedby the sequence preference to form base triplets). Mirror-repeats
occur randomly in prokaryotes, but are three to six times more frequent in eukaryotic genomes (Schroth
and Ho, 1995). Specific H-DNA forming sequences have been identified in multiple promoter regions with
documented effects on gene expression of several disease related genes, includingc-myc (Kinniburgh,
1989) and c-Ki-ras (Pestov et al., 1991). As with Z-DNA, the repeating sequence motif of H-DNA appears
to be a source of genetic instability resulting from double-strand breaks. Wang and Vasquez (2004)
reported a ~20 fold increase in mutation frequency upon incorporation of an H-DNA forming sequence
found in the c-myc promoter region into mammalian cells. These results suggest that naturally occurring
DNA sequences can cause increased mutagenesis via non-standard DNA structure formation.
Hairpins
Hairpin loops are formed by a fold in a single strand of DNA, causing several bases to remain
unpaired before the strand loops back upon itself. A hairpin loop is only possible if the strand of DNA
contains the complimentary bases in correct sequence to those that appear earlier in the strand. For
example; if a DNA strand contained CCGT followed by several bases including ACGG, the strand is
capable of creating a hairpin loop by folding back on itself.
Hairpin loops can occur in both DNA and RNA, though in RNA the thymine base is replaced by uracil.
The number of bases in the loop itself is variable, though it never exists in the length of three bases,
as the steric hindrance makes the configuration too unstable.
Here is an image example of hairpin DNA: (Image is of a Long-alpha hairpin)
Cruciforms
Cruciform DNA structure appears as several hairpin loops, creating a crucifix-like structure composed
of DNA.
DNA structure is formed by incomplete exchange of the strands between the double-stranded helices.
Cruciform DNA Eukaryotic cells contain DNA-binding protein that can specifically recognize cruciform
DNA. Interactions with ubiquitous protein plays a crucial role for the conformation of cruciform DNA.
An example of a DNA-binding Protein is Crp1p. This DNA-binding protein is found in the
yeast Saccharomyces cerevisiae
Image of the formation of Cruciform DNA can be found here.
Triple Helix
The triple helix form of DNA is similar to the double helix DNA except that it contains another
oligonucleotide that hydrogen bonds to the bases that are already included in the double helix strands
of DNA.
Background
The triple-stranded DNA was a very common hypothesis in the 1950s when scientists were having
trouble figuring out the true structure of DNA. Watson and Crick, Pauling and Corey all published a
triple-helix model proposal. Watson and Crick found problems with the model. The problems were as
follows:
1. Negatively charged phosphates near the axis will repel each other, leaving the question as to
how the three-chain structure would stay together.
2. In a triple-helix model (specifically Pauling and Corey's model), some of the van der Waals
distances appear to be too small.1
For more information on Triple-stranded DNA see DNA Triple-stranded DNA
An image of the triple helix form can be found here.
Hinged DNA
Hinged DNA (H-DNA) is a triple helix structure that exists based on hydrogen bonds between DNA
bases. The three strands base pair by Hoogsteen base pairing. Hoogsteeen base pairing is a
variation of base-pairing in the necleic acids such as the A-T pair or the G-C pair. The Hoogsteen
base pair applies the "N7 position of purine base and c6 amino group which bind the Waston-Crick
fafce of pyrimidine base." More information on the Hoogsteen base pair can be found here. It is also
called H-DNA because of its dependence on hydrogen bonds. The H-DNA can be found in vitro or
during recombination and also in DNA repair.
An example of H-DNA can be found here.
G-Quadruplex
G-quadruplexes are a family of quadruple-stranded structures formed by a guanine-rich sequences of
nucleic acids. Members of this family share a common square arrangement of four guanines centered
around a monovalent cation and stabilized by Hoogsteen hydrogen bonding. The guanines may adopt
either an anti or syn alignment about the glycosidic bond. The backbone strands of the g-tetrad can
also adopt a variety of directionalities: all four strands may be oriented in the same direction, three
strands are oriented in one direction while the fourth is in another direction, two adjacent strands can
be oriented in one direction while the other two will be oriented in another direction, or each strand will
have adjacent anti parallel neighbors. The sequence of amino acid that has the potential to form gquadruplex is: GxNaGxNbGxNcGx, where x is the number of G residues and Na, Nb, and Nc are
loops of different lengths. Furthermore, they can form in DNA, RNA, LNA, and PNA, and either be
intramolecular, bimolecular and tetramolecular compounds. Their four stranded motifs create four
grooves each with varying widths and depths. Their folding depends on many factors; DNA sequence,
presence of ions, temperatures, and presence of various ligands. They are a special area of interest
due to their biological implications specifically in telomeres and as contributors to gene regulation.
A shows a G-tetrad, B shows the Anti and Syn conformations of Guanine, C shows the various
directionailities of the backbone strands, D shows the different types of loops
Structure determination of G-quadruplex based on crystallography or solution NMR demonstrates
significant deviations in conformation and loop geometry suggesting heterogeneity in strand topology
and loop conformation of G-quadruplexes. Varying conformations can result in varying stability.
Furthermore, studies of the various conformations reveal that the nature of the loop sequence and the
formation of interactions between loops and the quadruplex core are important elements in controlling
quadruplex topology and stability. For example, in examining the bindinging of quinacridine-based
ligand to a G-quadruplex, interactions with the sides of the G-stack do not alter the topology but
interaction with the loop sequence ended up altering the conformation of the loops. This hints at the
notion that the loop sequences of the quadruplex are what actually moderate the binding affinity and
specificity of the whole structure.
The four-stranded structure with four grooves instead of the normal two found in typical DNA
structure, provides a variety of surfaces for interactions with ligands. Aromatic compounds of various
dimensions showed favorable interactions with the planer surfaces of terminal guanine tetrads.
Intercalation between layers of G-tetrads does not occur, however because G-tetrads do not allow for
bulky aromatic compounds to insert itself between layers of guanine.
In eukaryotic telomeres, there exists repeats of g-rich sequences that can fold into g tetrads. It has
been postulated that this structure plays an important role in cell aging and human diseases such as
cancer, then making them targets to anticancer drugs