G-Tetrad Core

G-quadruplex structures are polymorphic regarding the G-tetrad core and the loops. Recent G-quadruplex structures have been reported to contain a variety of new structural elements, as opposed to simpler structures that were reported or proposed a decade ago. This Chapter first describes and classifies the core and loop elements in G-quadruplexes, then examines several examples of recently reported structures. 

A G-tetrad core involves the stacking of several tetrads. The backbone strands (or columns) that support a tetrad can be of different orientations. There are four possibilities (i) four strands are oriented in the same direction (ii) three strands are oriented in one direction and the fourth in the opposite direction  

Besides the differences in strand orientations and synjanti conformations of guanines, G-tetrad cores can be polymorphic with respect to the continuity of the strands. In this regard, there are three major classes of G-tetrad core  

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Telomeric repeats from other organisms are also prone to quadruplex polymorphism. The Tetrahymena TG4T2G4T telomeric sequence, for example, may adopt several conformations. This sequence forms two novel G-quadruplex structures in Na -containing solution. In the first structure (head-to-head), the two loops are at one end of the G-tetrad core in the second structure (head-to-tail), the two loops are located on opposite ends of the G-tetrad core. In contrast to the human telomere sequence, the proportions of the two forms are similar for a wide range of temperatures their unfolding rates are also similar, with an activation enthalpy of 37 kcal mol . The (G4T4) sequence may also interconvert between parallel and antiparallel structures. 

V-shaped loops connecting two corners of a G-tetrad core in which one supporting column is lacking [Figure 2(d)]. The types of loops depend strongly on the size and sequence of the linkers. Diagonal loops eontain three or more residues.Besides one example of a quadruplex with mixed tetrads,in... 

The d(A2G2T4A2G2) sequence forms a diamond-shaped dimeric G-quadru-plex" with diagonal loops (Figure 4). Formation of a T (A-A) triad [Figure 4(c)] was observed in the A2T4 diagonal loops. This triad is stabilized by stacking on the G-tetrad core. 

Figure 14 Examples of interrupted G-tetrad cores in G-quadruplex structures from (a) ref 24, (b) ref 23, (c) ref 46, and (d) ref 50. The break points are highlighted by arrows. Relative sugar orientations across the break are (a, b) 5 -to-5, (c) 3 -to-3, and (d) 5 -to-3 ...

The structure of the bulged G-tetrad core can be considered as an intermediate between the continuous and the interrupted cores mentioned above. Figure 14 shows different examples of interrupted G-tetrad cores. The relative sugar orientations between two residues across the break point can be (i) 5 -to-5 (Figure 14a and b) (ii) 3 -to-3 [Figure 14(c)] and (hi) 5 -to-3 [Figure 14(d)]. 

G-quadruplex architectures can contain a large variety of G-tetrad core and loop elements. This structural polymorphism depends strongly on sequences and experimental conditions, such as the nature of cations. Some general rules for G-quadruplex folding have emerged, such as the robustness of the... 

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