Structural Biochemistry/Nucleic Acid/DNA/DNA structure/Unusual Structures

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DNA does not always take the form of a double helix. It can often be found creating structures considered abnormal when compared to what is commonly considered DNA. Normally, DNA contains a B-form helix. Improper formation of base pairs can greatly affect DNA's structure and flexibility.

Single-stranded nucleic acids can form hairpins. Such formations can affect the transcription terminations in prokaryotes. With regard to double-stranded DNA, they can form something called cruciforms.


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) PDB 2qoz EBI.png


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[edit]

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.

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[edit]

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 nucleic 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 face 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-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 g-quadruplex 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.


  1. Problems with triple helix model: <>
  2. H-DNA: <>
  3. Cruciform DNA: <>
  4. Sannohe,Yuta, Sugiyama, Hiroshi. "Overview of Formation of G-Quadruplex Structures" Wiley Online Library. 01 Mar. 2010. 20 Nov. 2010.
  5. Martin Egli, Pradeep S Pallan. "The many twists and turns of DNA: template, telomere, tool, and target" Current Opinion in Structural Biology. 08 Apr. 2010. 20 Nov. 2010
  6. Lubos Bauer,Peter Javorsky, Katarina Tluckova, and Viktor Viglasky. "Evaluation of human telomeric g-quadruplexes: the influence of overhanging sequences on quadruplex stability and folding" Journal of Nucleic Acid. 10 Jun. 2010. 20 Nov. 2010