Why Adenine Does Not Pair With Cytosine

V H-bond donor ^ H-bond acceptor

FIGURE 6-5 Base tautomers. Amino ~ imino and keto ^ enol tautomerisrr. (a)Cyto sine ts usually m the amino form but rarely forms the imino configuration, (b) Guanine is usually in rhe keto form bin is rarely found in the enot configuration

The Two Chains of the Double Helix Have Complementary Sequences

The pairing between adenine and thymine, and between guanine and cytosine, results in a complementary relationship between the sequence of bases on the two intertwined chains and gives DNA its self-encoding character. For example, if we have the sequence 5'-ATCTC-3' on one chain, the opposite chain must have the complementary sequence 3'-TACAC-5\

The strictness of the rules for this "Watson-Crick" pairing derives from the complementarity both of shape and of hydrogen bonding properties between adenine and thymine and between guanine and cytosine (Figure fi-6). Adenine and thymine match up so that a hydrogen bond can form between the exocyclic amino group at C6 on adenine and the carbonyl at C4 in thymine; and likewise, a hydrogen bond can form between Nl of adenine and N3 of thymine. A corresponding arrangement can be drawn between a guanine and a cytosine, so that there is both hydrogen bonding and shape complementarity in this base pair as well. A G:C base pair has three hydrogen bonds, because the exocyclic NH, at C2 on guanine lies opposite to, and can hydrogen bond with, a carbonyl at C2 on cytosine. Likewise, a hydrogen bond can form between N't of guanine and N3 of cytosine and between the carbonyl at C6 of guanine and the exocyclic NR, at C4 of cytosine. Watson-Crick base pairing requires that the bases are in their preferred tautomeric, states.

An important feature of the double helix is that the two base pairs have exactly the same geometry; having an A:T base pair or a G;C base pair between the two sugars does not perturb the arrangement of the sugars because the d¡stance between the sugar attachment points are the same for both base pairs. Neither does T:A or C:G. In other words,

sugar

FIGURE 6-6 A:Tand C:C base pairs.

The figure shows hydrogen bonding between (he bases.

FIGURE 6-6 A:Tand C:C base pairs.

The figure shows hydrogen bonding between (he bases.

there is an approximately twofold axis of symmetry that relates the two sugars and all four base pairs can be accommodated within the same arrangement without any distortion of the overall structure of the DNA. In addition, the base pairs can stack neatly on top of each other between the two helical sugar-phosphate backbones.

sugar

fVi sugar

FIGURE 6-7 A:C incompatibility, the structure shows the inability of adenine to form the proper hydrogen bonds with cytosine the base parr is therefore unstable.

Adenine And Cytosine Incompatibility
FIGURE 6-fl Base flipping. Structure of isolated DMA, showing the flipped cytosine residue and the small distortions to the adjacent base pairs. (Ktimasauskas S, Kumar 5., Roberts R.J., and Cheng X. 1994. Cell 76 357. Image prepared with BobScnpt, MolScripi, and Raster 3D )

Hydrogen Bonding Is Important for the Specificity of Base Pairing

The hydrogen bonds between complementary bases are a fundamental feature of the double helix, contributing to the thermodynamic stability of the helix and the specificity of base pairing. Hydrogen bonding might not, at first glance, appear to contribute importantly to the stability of DMA for the following reason. An organic molecule in aqueous solution has all of its hydrogen bonding properties satisfied by water molecules that come on and off very rapidly. As a result, for every hydrogen bond that is made when a base pair forms, a hydrogen bond with water is broken that was there before the base pair formed. Thust the net energetic contribution of hydrogen bonds to the stability of the double helix would appear to be modest. However, when polynucleotide strands are separate, water molecules are lined up on the bases. When strands come together in the double helix, the water molecules are displaced from the bases. This creates disorder and increases entropy, thereby stabilizing the double helix. Hydrogen bonds are not the only force that stabilizes the double helix. A second important contribution comes from stacking interactions between the bases. The bases are flat, relatively water-insoluble molecules, and they tend to stack above each other roughly perpendicular to the direction of the helical axis. Electron cloud interactions (it— tr) between bases in the helical stacks contribute significantly to the stability of the double helix.

Hydrogen bonding is also important for the specificity of base pairing. Suppose we tried to pair an adenine with a cytosine. Then we would have a hydrogen bond acceptor (Nl of adenine) lying opposite a hydrogen bond acceptor (N3 of cytosine) with no room to put a water molecule in between to satisfy the two acceptors (Figure 6-7), Likewise, two hydrogen bond donors, the NH; groups at C6 of adenine and C4 of cytosine, would lie opposite each other. Thus, an A:C base pair would be unstable because water would have to be stripped off the donor and acceptor groups without restoring the hydrogen bond formed within the base pair.

Bases Can Flip Out from the Double Helix

As we have seen, the energetics of the double helix favor the pairing of each base on one polynucleotide strand with the complementary base on the other strand. Sometimes, however, individual bases can protrude from the double helix in a remarkable phenomenon known as base flipping shown in Figure 6-B. As we shall see in Chapter 9, certain enzymes that methylate bases or remove damaged bases do so with the base in an extra-helical configuration in which it is flipped out from the double helix, enabling the base to sit in the catalytic cavity of the enzyme. Furthermore, enzymes involved in homologous recombination and DNA repair are believed to scan DNA for homology or lesions by flipping out one base after another. This is not energetically expensive because only one base is Hipped out at a time. Clearly, DNA is more flexible than might be assumed at first glance.

DNA Is Usually a Right-Handed Double Helix

Applying the handedness rule from physics, we can see that each of the polynucleotide chains in the double helix is right-handed. In your mind's eye, hold your right hand up to the DNA molecule in Figure 6-9 with your thumb pointing up and along the long axis of the helix and your fingers following the grooves in the helix. Trace along one strand of the helix in the direction in which your thumb is pointing. Notice that yuu go around the helix in the same direction as your fingers are pointing. This does not work if yuu use your left hand. Try it!

A consequence of the helical nature of DNA is its periodicity. Each base pair is displaced (twisted) from the previous one by about 36c. Thus, in the X-ray crystal structure of DNA it takes a stack of about 10 base pairs to go completely around the helix (360L) (see Figure 6-la). That is, the helical periodicity is generally 10 base pairs per turn of the helix. For further discussion, see Box 6-1, DI\A Has 10,5 Case Pairs per Turn of the Helix in Solution: The Mica Experiment.

The Double Helix Has Minor and Major Grooves

As a result of the double-helical structure of the two chains, the DNA molecule is a long extended polymer with two grooves that are not equal in size to each other. Why are there a minor groove and a major groove? Tt is a simple consequence of the geometry of the base pair. The angle at which the two sugars protrude horn the base pairs (that is, the angle between the glycosidic bonds) is about 120° (for the narrow angle or 240" for the wide angle) (see Figures 6-lb and 6-6). As a result, as more and more base pairs stack on top of each other, the narrow angle between the sugars on one edge of the base pairs generates a minor groove and the large angle on the other edge generates a major groove. (If the sugars pointed away from each other in a straight line, that is, at an angle of 180'\ then the two grooves would be of equal dimensions and there would be nu minor and major grooves.)

The Major Groove Is Rich in Chemical Information

The edges of each base pair are exposed in the major and minor grooves, creating a pattern of hydrogen bond donors and acceptors and of van der Waals surfaces that identifies the base pair (see Figure 6-10). The edge of an A:T base pair displays the following chemical groups in the following order in the major groove: a hydrogen bond acceptor (the N7 of adenine), a hydrogen bond donor (the exocyclic amino group on C6 of adenine), a hydrogen bond acceptor (the carbunyl group on C4 of

FIC U ft E 6-9 Left- and right-handed helices. The two polynucleotide chains in the double helix wrap around one another in a ngbt handed manner.

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    Why adenine does not pair with cytosine?
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