Nucleic Acids: DNA and RNA Chemistry

Every living thing stores the instructions for building itself in molecules called nucleic acids. DNA holds the long-term archive; RNA copies out working instructions and helps turn them into proteins. Biology textbooks usually describe what nucleic acids do. This article looks at what they are: the atoms, bonds and chemical properties that make them so well suited to storing and using information.

The building block: the nucleotide

Nucleic acids are polymers, and their monomers are nucleotides. Each nucleotide has three parts:

1. A five-carbon sugar (a pentose).
   • In DNA it’s deoxyribose.
   • In RNA it’s ribose. The only difference is at carbon 2′: ribose has an –OH group there, while deoxyribose has just a hydrogen (“deoxy” means “missing an oxygen”). See monosaccharides for more on pentose sugars.
2. A phosphate group, attached to carbon 5′ of the sugar.
3. A nitrogen-containing base, attached to carbon 1′ of the sugar.

(The carbons of the sugar are numbered with primes, 1′ to 5′, to distinguish them from the atoms of the base.)

A sugar plus a base, without the phosphate, is called a nucleoside. Add one or more phosphate groups and it becomes a nucleotide. ATP, the cell’s energy carrier, is a nucleotide: adenine + ribose + three phosphates.

The five bases

The bases are flat, ring-shaped molecules containing nitrogen. There are two families:

Family	Structure	Bases	Found in
Purines	Two fused rings (a six- and a five-membered ring)	Adenine (A), Guanine (G)	DNA and RNA
Pyrimidines	One six-membered ring	Cytosine (C)	DNA and RNA
		Thymine (T)	DNA only
		Uracil (U)	RNA only

A memory aid: “Pure As Gold” for purines (A, G), and pyrimidines are the ones with “y” in their names (cytosine, thymine) plus uracil.

Thymine and uracil differ only by one methyl group: thymine has a –CH₃ at one position where uracil has a hydrogen. That small difference turns out to help DNA’s accuracy: cytosine can slowly lose an amino group and turn into uracil. Because DNA normally uses thymine, any uracil found in DNA is recognised as damage and repaired.

The bases are called “bases” because their nitrogen atoms can accept protons, although in practice they’re only weakly basic. What matters most is that they can form specific hydrogen bonds with each other: A with T (or U), and G with C (see base pairing).

Linking nucleotides: the phosphodiester bond

Nucleotides join together through condensation reactions. The phosphate group attached to carbon 5′ of one nucleotide bonds to the –OH group on carbon 3′ of the previous one, releasing water. The resulting link, a phosphate bonded to two sugars, is a phosphodiester bond (a phosphate with two ester links).

Repeating this makes a long chain with:

• a sugar–phosphate backbone of alternating sugars and phosphates;
• bases sticking out from the backbone, one per sugar.

The backbone is identical all along the chain; the information is carried entirely by the sequence of bases. This is a neat chemical design: a uniform, sturdy backbone for strength, and a variable side group for information.

(In cells, the building blocks are actually nucleoside triphosphates, and the energy for joining them comes from breaking off two of the phosphates. That detail is covered in DNA replication: the chemistry.)

Direction: 5′ and 3′ ends

Because each link goes from carbon 3′ of one sugar to carbon 5′ of the next, a nucleic acid chain has direction:

• the 5′ end has a free phosphate on carbon 5′;
• the 3′ end has a free –OH on carbon 3′.

Sequences are always written from 5′ to 3′, for example 5′-ATGCCTAG-3′. Enzymes that build nucleic acids always add new nucleotides to the 3′ end, so chains grow in the 5′→3′ direction. This directionality turns out to be crucial for how DNA is copied and read.

Why nucleic acids are acids

Each phosphate group in the backbone has one acidic –OH group left after forming its two ester bonds. Its pKa is about 1, so at the pH of a cell it has lost its proton and carries a negative charge. A DNA molecule therefore has one negative charge per nucleotide, which is why it’s called an acid, and why:

• DNA is very soluble in water;
• DNA binds tightly to positively charged proteins such as histones, which package it in the nucleus;
• DNA moves towards the positive electrode in gel electrophoresis, where fragments are separated by size (see electrophoresis);
• magnesium ions and other cations are needed to shield the negative charges and stabilise nucleic acid structures.

Adding ethanol to a salty DNA solution makes the DNA come out of solution as white strands, the basis of the classic “extract DNA from strawberries” experiment.

DNA and RNA: two jobs, two structures

DNA (deoxyribonucleic acid)

• Double-stranded: two chains wound into a double helix, running in opposite directions, held together by hydrogen bonds between paired bases (see the structure of DNA).
• Very long: a single human chromosome contains one DNA molecule with tens to hundreds of millions of base pairs.
• Stable: the missing 2′-OH makes the backbone much more resistant to hydrolysis than RNA’s.
• Job: long-term storage of genetic information.

RNA (ribonucleic acid)

• Usually single-stranded, but it folds back on itself to form short double-stranded regions and complex 3D shapes.
• Shorter and more temporary than DNA.
• Less stable: the 2′-OH group can attack the neighbouring phosphodiester bond, especially in alkaline conditions, so RNA breaks down more easily.
• Jobs: several.
  • Messenger RNA (mRNA) carries copies of genes to the ribosomes.
  • Transfer RNA (tRNA) brings amino acids to the ribosome.
  • Ribosomal RNA (rRNA) forms the core of ribosomes and catalyses peptide bond formation.
  • Many other RNAs regulate genes.

A full comparison is in DNA vs RNA.

Nucleic acids by the numbers

• The human genome contains about 3.1 billion base pairs in each set of chromosomes.
• Stretched out, the DNA in one human cell would be about 2 metres long, packed into a nucleus a few micrometres across.
• The DNA double helix is about 2 nm wide, with about 10.5 base pairs per turn.

Nucleic acids in medicine and technology

• PCR (polymerase chain reaction) copies small amounts of DNA millions of times, for diagnosis, forensics and research (see forensic chemistry).
• mRNA vaccines deliver instructions for a harmless viral protein, wrapped in lipid nanoparticles to protect the fragile RNA.
• Antiviral drugs such as some HIV and hepatitis treatments are modified nucleosides that are built into viral DNA or RNA and stop the chain from growing.
• DNA sequencing reads the order of bases, now fast and cheap enough to sequence whole genomes routinely.

Key takeaways

• Nucleic acids are polymers of nucleotides: a pentose sugar, a phosphate and a nitrogenous base.
• DNA uses deoxyribose and bases A, T, G, C; RNA uses ribose and A, U, G, C.
• Nucleotides are joined by phosphodiester bonds, forming a sugar–phosphate backbone with bases carrying the information.
• Chains have a 5′ end and a 3′ end, and grow in the 5′→3′ direction.
• Each backbone phosphate carries a negative charge, making nucleic acids acidic, water-soluble and attracted to positive proteins. See where they fit among biomolecules in the four major biomolecules.