Nucleic acid folding patterns are dominated by base pairing, which results from the formation of hydrogen bonds between pairs of nucleotides. In nucleic acids, as in proteins, the highly directional nature of this hydrogen bonding is the key to secondary structure.
What is the basis for this directionality?
Hydrogen bonds are highly directional because the interacting atoms (e.g. O–H–N) must lie in an approximately straight line for strong bonding.
The hydrogen bonding between complementary base pairs in a duplex (double-stranded) molecule is shown in Figure 5a. Note that the cytosine–guanine (C–G) coupling incorporates three hydrogen bonds and is therefore stronger than the adenine–thymine (A–T) coupling, with only two hydrogen bonds. Similarly, in RNA, the A–U base pair has two hydrogen bonds. As a general rule, nucleic acid chains tend to fold so as to maximise base pairing. This folding produces two common secondary structures found in vivo, the double helix (or duplex) in DNA, and the hairpin in RNA. The base pairing just described lends itself to long stretches of regular, hydrogen-bond-stabilised nucleic acid folding patterns, comparable to the secondary structures of proteins. It was by appreciating the significance of these G–C and A–T base pairs that Watson and Crick were able to come up with their model of the DNA double helix, in their famous Nature paper of 1953, from which the term Watson-Crick pairing arose.
X-ray diffraction of nucleic acids has revealed several examples of base pairing that do not conform to the G–C /A–T pairing described by Watson and Crick. One example, to be described in a later section, is the G–G pair found in telomeric DNA. This non-Watson-Crick base pairing produces a characteristic three-dimensional shape that stabilises specialised nucleic acid structures and is recognised by nucleic acid binding proteins. Poorly matched base pairs (for example, A–C and G–T), in which the hydrogen-bonded atoms are imperfectly aligned, also insert extra flexibility at specific sites in RNA chains. Another example of a common ‘mispair’ is G–U, shown in Figure 5b. G–U pairing is found in the codon-anticodon interaction in the ribosome.