User:Sawagsta/New sandbox

= Non-canonical base pairing = Non-canonical base pairing refers to instances in which nucleobases hydrogen bond, or base pair, to one another in schemes other than the Watson-Crick base pairs (adenine-thymine in DNA, adenine-uracil in RNA, and guanine-cytosine in both DNA and RNA).

Non-canonical base pairings commonly occur in the secondary structure of RNA (e.g. pairing of G with U), and in tRNA recognition. They are typically less stable than standard base pairings. The presence of non-canonical base pairs in double stranded DNA results in a disrupted double helix.

History
James Watson and Francis Crick published the double helical structure of DNA and proposed the canonical Watson-Crick base pairs in 1953. Ten years later, in 1963, Karst Hoogsteen reported alternative structures for the nucelobase pair adenine-thymine in which the purine (adenine) takes on an alternative conformation with respect to the pyrimidine(thymine). The adenine is rotated 180° about the glycosidic bond, resulting in an alternative hydrogen bonding scheme which has one hydrogen bond in common with the Watson-Crick base pair (adenine N6 and thymine N4), while the other, instead of occurring between adenine N1 and thymine N3 as in the Watson-Crick base pair, occurs between adenine N7 and thymine N3. Five years after Hoogsteen proposed the A-T Hoogsteen base pair, evidence for a G-C Hoogsteen base pair was published. Similarly to the A-T Hoogsteen base pair, the purine (guanine) is rotated 180° about the glycosidic bond while the pyrimidine (cytosine) remains in place. One hydrogen bond from the Watson-Crick base pair is maintained (guanine O6 and cytosine N4) and the other occurs between guanine N7 and a protonated cytosine N3 (note that the Hoogsteen G-C base pair has two hydrogen bonds, while the Watson-Crick G-C base pair has three). Ultimately, after years of studying both Watson-Crick and Hoogsteen base pairs, it has been determined that both occur naturally in DNA, and that they exist in equilibrium with one another; the conditions in which the DNA exists ultimately determine which form will be favored.

Since the structures of the canonical Watson-Crick and non-canonical Hoogsteen base pairs were determined, many other types of non-canonical base pairs have been presented and described. Types of non-canonical base pairs can be defined by which faces of the nucleobases are interacting in a given base pair. When classified this way, nearly 40 types of non-canonical base pairs can be identified. These can be sorted into the larger categories of cis and trans.

Base pairing
60% of the paired bases in RNA structures are the canonical Watson-Crick base pairs with the remaining being non-canonical base pairs. Each base has three potential edges where it can interact with another base. Those are the Watson-Crick edge, the Hoogsteen edge or "C-H" edge, and the sugar edge. This interaction can occur in both the cis and the trans conformation. The most common non-canonical base pairs are trans A:G Hoogsteen/sugar edge, A:U Hoogsteen/WC, and G:U Wobble pairs.

Understanding the base pair configuration is difficult since the pairing is very dependent on the bases surroundings. The pairs configuration could be interacting with loops or other adjacent basepairs in the RNA strand. Due to the rigid planar molecules the bonding between the bases must have certain interactions. These interactions can be classified in 6 rigid-body parameters(3 translational, 3 rotational). The three translational arrangements are known as shear, stretch, and stagger when the rotational arrangements are buckle, propeller, and opening. These parameters were originally created for the base pairings in DNA but can also fit the non-canonical base models.

The many base pairings and conformations have also led to many softwares designed to interpret crystallography data to determine the structure of the various base pairings. Scientist are also working on developing a nomenclature or system to organize the corresponding base pairs.

Three-Dimensional Structure
Three-dimensional structures of RNA are possible due to non-canonical base pairs. Base pairs make up many secondary structural blocks which aid the folding of RNA complexes and three dimensional structures. Due to the many non-canonical base pairs there are an unlimited amount of structures which allow for the diverse functions of RNA. The arrangement of the non-canonical bases allow long-range RNA interactions, recognition of proteins and other molecules, and structural stabilizing elements. Many of the common non-canonical base pairs can be added to a stacked RNA stem without disturbing its helical character. The three-dimensional structures of RNA are primarily determined through molecular simulations or computationally guided measurements. Research is still continuing to detect, characterize, and simulate spatial properties of three-dimensional RNA structures.

Biological Applications
RNA has many purposes throughout the cell including many important steps in gene expression. Various conformations of the non-Watson-Crick base pairs allow for a multitude of biological functions such as mRNA splicing, siRNA, transport, and translation. One example of this is in the HIV-1 Rev-response element (RRE) RNA. Due to the extra wide deep groove in the RNA that is caused by cis Watson-Crick G:A pair followed by a trans Watson-Crick G:G the peptide is able to bind due to the deepened groove. This is one of the many examples of how essential these non-canonical base pairs are in various biological functions.