Opening Image: Surface model of homo-DNA, an artificial analog of DNA in which the usual five-carbon sugar has been replaced with a six-carbon sugar. For clarity, 67 out of 72 water molecules were omitted from the model. One Mg²⁺ is coordinated to five water molecules, shown in spacefill.

When you learned about DNA as the code of life, you may or not have heard anything about the sugars in DNA or RNA. Then somewhere along the way you learned that the "D" stands for deoxyribose and that the "R" stands for ribose. But have you ever stopped to wonder why Nature chose pentoses for the genetic system?

Your assignment, should you choose to accept it, is to answer this question for yourself by carrying out the following instructions. You'll find background information here.

Review: Ribonucleotides vs. 2′-deoxyribonucleotides

Question 1: Identify the following nucleotides.

Question 2: Identify the anomeric carbon in each pentose in the above nucleotides and report its number. You can find the atom number, assigned by JSmol, by hovering your cursor over the atom of interest, or turning labels on.

2′-deoxyribose vs. 2′,3′-dideoxyglucose

The β anomer of 2′,3′-dideoxyglucose. Recall that the anomeric carbon is easily identified as the only carbon bonded to two oxygen atoms. In the β anomer, the anomeric –OH group is equatorial, whereas it is axial in the α anomer.

The prefix "homo" refers to a homolog; this term has the precise chemical definition having one additional carbon atom. In other words, 2′,3′-dideoxyglucose is a homolog of 2′-deoxyribose.

Let's see what happens when we replace the of the sugar-phosphate backbone of a oligodeoxynucleotide with .

Building Blocks for Homo-DNA

To construct a homo-DNA molecule (DNA with one additional carbon atom in each nucleotide), you string homo-nucleotides together using 6′→4′ phosphodiester linkages. By linking 2′,3′-dideoxyglucose to the nucleobases A, G, T, and C, you can assemble a new series of nucleotides. We'll call these homo-nucleotides.

space-filled model. Sure looks like an ordinary nucleotide, that is until you realize there are six atoms in the sugar ring.

The base in a nucleotide is linked to the sugar-phosphate backbone by an N-glycosidic bond to the C1′ of the sugar; the configuration of the glycosidic linkage is always β.

Question 3: Explain why nucleotides are always β-N-glycosides. Please base your answer on the JSmol model.

Note: Bases are joined to the pentose sugars via an N-glycosidic linkage to the anomeric carbon of the sugar. In an N-glycoside, the anomeric carbon of the sugar is attached to the ring oxygen atom and the nitrogen atom of an amine or, in the case of nucleic acids, to one of the ring nitrogens of the base.

Constructing a Stable Homo-DNA "Double Helix"

As you know, the 5′-phosphate group of one nucleotide unit is joined to the 3′-hydroxyl group of the next nucleotide, creating a 5′→3′ phosphodiester linkage. Thus, the backbones of nucleic acids consist of alternating phosphate and pentose residues and, as such, contain no genetic information. All the information carried by a nucleic acid resides in the sequence of bases, which are covalently attached to the backbone via N-glycosidic bonds. Thus, we can regard the bases as side chains extending out from the backbone.

Returning to homo-DNA, Eschenmoser's group has synthesized an octamer using homo-nucleotides. The sequence of bases in the 8-mer is such that two strands are self-complementary. Therefore, in principle, the two strands can form a double helix through Watson-Crick base pairing.

In fact, the octameric homo-DNA forms a dimer which is more stable than the DNA. Its 3D structure was determined by X-ray crystallography in 2006. Let's look the crystal structure, starting with the overall structure and then the sugar-phosphate backbone.

Surface model of homo-DNA containing two self-complementary strands of homo-nucleotides. Chains A and B are shown in violet and purple, respectively.

the sugar-phosphate backbone. For clarity, hydrogen atoms and those atoms of the hexose which are not part of the backbone per se are omitted.

For homo-DNA the 6′-phosphate group of one homo-nucleotide is connected to the 4′-hydroxyl group of the next homo-nucleotide (6′→4′). However, it is important to note that the number of atoms in the backbone of either DNA or homo-DNA is the same. In other words, both backbones are identical and both have the same flexibility. In either molecule, the sugar ring prevents rotation around one C–C bond in the backbone. Otherwise, both backbones are flexible and allow the chain to adopt a number of conformations.

between ball-and-stick and spacefilled models of the dimeric molecule.

Analyzing the Model

The space-filled model of homo-DNA clearly shows that the dimer does not adopt the compact structure characteristic of B-DNA. Sequence-dependent structural variations in DNA are well known. So it would a good idea to analyze the homo-DNA more closely.

First, you need to confirm that the two strands self-complementary. Remember that, by convention, the structure of a single strand of nucleic acid is always written in the 5′→3′ direction, or in the case of homo-DNA, from the 6′ end to the 4′ end.

Question 5: Identify the 4′-OH and 6′-OH ends of each strand and report the numbers of the oxygen atoms.

Question 6: Write the sequence of each strand. Are the bases in each strand complementary to each other?

Question 7: Which strand is ligated to magnesium? Describe the coordination of Mg²⁺?

Question 8: Why did Nature chose pentose over hexose in the nucleic acids?