Nucleic acid structure

Nucleic acid structure describes the arrangement of molecules like DNA and RNA. DNA and RNA are chemically alike. Their structure is typically broken into four levels: primary, secondary, tertiary, and quaternary.

**Primary structure**

The primary structure is a linear chain of nucleotides connected by phosphodiester bonds. This chain forms the backbone of DNA or RNA. Each nucleotide has three parts: a nitrogenous base, a five-carbon sugar, and one or more phosphate groups. The bases are adenine, guanine, cytosine, thymine (only in DNA), and uracil (only in RNA). The sugar is deoxyribose in DNA and ribose in RNA. Purine bases (adenine and guanine) link to the sugar’s 1' carbon via their 9 nitrogen. Pyrimidine bases (cytosine, thymine, uracil) link via their 1 nitrogen. The phosphate group bonds to the sugar’s 5' carbon through an ester link. Polarity in the backbone comes from oxygen and nitrogen atoms. Nucleotides join through phosphodiester bonds between the 5' and 3' carbons.

A nucleic acid sequence is the order of nucleotides, written from the 5' to 3' end. For DNA, the letters are G, A, C, T; for RNA, G, A, C, U. Sequences can be complementary: each base pairs with a specific partner, and the order is reversed. For example, the complement of AGCT is TCGA. DNA is double-stranded, with a sense strand and an antisense strand; the complementary sequence matches the sense strand.

Alkali metal ions can bind to nucleic acids at three sites: phosphate groups, sugar groups, and base groups. The solid-state structures of these complexes have been reviewed.

**Secondary structure**

In DNA, secondary structure involves interactions between bases—which parts of strands bind together. In the double helix, two strands are held by hydrogen bonds between base pairs. Purines (adenine and guanine) have a double-ring structure; pyrimidines (cytosine and thymine) have a single ring. A purine always pairs with a pyrimidine: guanine with cytosine, and adenine with thymine (or uracil in RNA). The double helix forms when two polynucleotide strands wrap around each other. While hydrogen bonds align the base pairs, stronger stacking interactions between bases—stabilized by van der Waals forces and hydrophobic effects—hold the strands together. These stacking interactions vary locally. The helix has two grooves: the major groove and the minor groove.

In RNA, secondary structure comes from a single polynucleotide chain. Base pairing occurs when the RNA folds back on itself at complementary regions. RNA molecules often contain both single- and double-stranded sections. The four basic elements are helices, bulges, loops, and junctions. Antiparallel strands form a helical shape. Bulges and internal loops arise when unpaired nucleotides separate the double helix on one strand (bulge) or both strands (internal loop). The most common element is a stem-loop (or hairpin loop), where the chain folds back to form a double-stranded stem and a single-stranded loop. A tetraloop is a four-base hairpin structure. Three common tetraloop families in ribosomal RNA are UNCG, GNRA, and CUUG (N is any nucleotide, R is a purine); UNCG is the most stable. A pseudoknot is a secondary structure first found in turnip yellow mosaic virus. It has at least two helical segments connected by single-stranded regions or loops. In the H-type fold, nucleotides in a hairpin loop pair with bases outside the stem, creating a second stem and loop, forming two stems and two loops. Pseudoknots are functional elements in many RNA classes. RNA secondary structure can be predicted from experimental data on helices, loops, and bulges. The DotKnot-PW method compares similarities in stems, secondary elements, and H-type pseudoknots to predict pseudoknots.

**Tertiary structure**

Tertiary structure is the three-dimensional arrangement of atoms, accounting for geometric and steric limits. It is a higher order than secondary structure, involving large-scale folding of the linear polymer into a specific 3D shape. DNA can differ in four structural areas, one of which is handedness.