Section 23.3.2.2. Sugar ring conformations

The type of ligand–ligand clash just mentioned is an important element in ensuring that five-membered rings, such as ribose and deoxyribose, are not ordinarily planar, even though the internal bond angle of a regular pentagon, 108°, is close to the 109.5° of tetrahedral geometry. A stable compromise is for one of the four ring atoms to lie out of the plane defined by the other four, as in Fig. 23.3.2.4. This is termed an `envelope' or E conformation, by analogy with a four-cornered envelope having a flap at an angle. Intermediate `twist' or T forms are also possible, in which two adjacent atoms sit on either side of the plane defined by the other three, but this discussion will focus on the simple envelope conformations. In most cases, the accuracy of a nucleic acid crystal structure determination is such that it would be difficult to distinguish clearly between a given E form and its flanking T forms. For this reason, most structure reports consider only the E alternatives.

Figure 23.3.2.4| top | pdf | The three most common furanose ring geometries. The planar form of the five-membered ribose or deoxyribose ring is unstable because of steric hindrance from side groups; one of the five atoms prefers to pucker out-of-plane on one side of the ring or the other. Puckering toward the same side of the ring as the C5′ atom is termed endo, and puckering toward the opposite `outside' surface is termed exo. The main-chain torsion angle δ is related to sugar ring conformation because of the motion undergone by the C3′—O3′ bond during changes in puckering.

A convenient and intuitive nomenclature is to name the conformation after the out-of-plane atom and then specify whether it is out of plane on the same side as the C5′ atom (endo) or the opposite side (exo). Ten such conformations exist: five endo and five exo. In Fig. 23.3.2.4 (top), pushing the C3′ atom of the C3′-endo conformation into the plane of the ring would tend to push C2′ below the ring, passing through a T state and creating a C2′-exo conformation. C2′ can, in turn, be returned to the ring plane if C1′ is pushed above the ring, forming C1′-endo, and so on, around the ring. In this way, a contiguous series of alternating endo/exo conformations is produced, as listed in Table 23.3.2.2.

This ten-conformation endo/exo cycle can be generalized to a continuous distribution of intermediate conformations, characterized by a pseudorotation angle, P (Altona et al., 1968; Altona & Sundaralingam, 1972), with the ten endo/exo conformations spaced 36° apart (Table 23.3.2.2). Fig. 23.3.2.5 shows the calculated potential energy of conformations around the pseudorotation cycle (Levitt & Warshel, 1978). Note that C2′-endo and C3′-endo are most stable, that the pathway between them along the right half of the circle remains one of low energy, but that a large 6 kcal mol⁻¹ potential energy barrier (1 kcal mol⁻¹ = 4.184 kJ mol⁻¹) effectively forbids conformations around the left half of the circle.

Figure 23.3.2.5| top | pdf | Potential plot of all furanose ring conformations. Energies are in kcal mol −1. The distance from the central point gives the maximum displacement of the out-of-plane atom from the plane of the other four. The circle is a constant-displacement trajectory chosen to pass through the potential minima on the right three-quarters of the plot. C2′-endo and C3′-endo are especially favoured, whereas O1′-exo on the left is highly disfavoured. The path from C2′-endo through C1′-exo, O1′-endo and C4′-exo to C3′-endo is a low-energy path, and many examples all along this path are known in B-DNA helices. Reprinted with permission from Levitt & Warshel (1978). Copyright (1978) American Chemical Society.

As Fig. 23.3.2.4 indicates, the main-chain torsion angle, δ, is sensitive to ring conformation, because the C5′—C4′ and C3′—O3′ bonds that define the angle shift as ring puckering changes. The idealized relationship between torsion angle, δ, and pseudorotation angle, P (Saenger, 1984), is Fig. 23.3.2.6 shows the observed torsion angles, δ, and pseudorotation angles, P, from X-ray crystal structure analyses of synthetic DNA oligonucleotides: 296 examples from A-DNA and 280 from B-DNA. The most striking aspect of this plot is the radically different behaviour of A- and B-DNA. The prototypical sugar conformation for A-DNA obtained from fibre diffraction modelling, C3′-endo, is, in fact, adhered to quite closely in A-DNA crystal structures.

Figure 23.3.2.6| top | pdf | Plot of observed sugar conformations in 296 nucleotides of A-DNA (crosses) and 280 of B-DNA (open circles). Open squares mark ideal relationships between torsion angle δ (vertical axis) and pseudorotation angle P (horizontal axis) from the expression . Deviations from this ideal curve for real helices arise, because the amplitude of pseudorotation (or displacement of one atom from the mean plane of the others) varies from one ring to another. Note the tight clustering of A-DNA points around C3′-endo and the broader distribution of B-DNA conformations.

However, B-DNA shows a quite different behaviour. Although earlier fibre diffraction led one to expect C2′-endo sugars, the actual experimental distribution is quite broad, extending up the right-hand side of the pseudorotation circle of Fig. 23.3.2.5, through C1′-exo, O1′-endo and C4′-exo, in some cases all the way to C3′-endo itself. Indeed, the mean value of δ observed in B-DNA oligomer crystal structures is 128° rather than 144° (Table 23.3.2.1), making C1′-exo a better description of sugar conformation in B-DNA than C2′-endo. Old habits die hard, however, and the B-DNA sugar conformation is still colloquially termed C2′-endo, a designation of historical significance but of little practical value. The apparent greater malleability of the B helix compared to A may indeed be one feature that makes B-DNA particularly suitable for expressing its base sequence to drugs and control proteins via local helix structure changes.