structures for G-tetrads have only emerged recently. Dinshaw Patel and co-workers determined the structure
of the tetraplex adopted by the human telomeric repeat d(AG 3 (T 2 AG 3 ) 3 ) in the presence of sodium ions by
solution NMR. Under these conditions, the 22 mer adopts a four-stranded motif with three G 4 layers and
lateral and diagonal loops. The four strands alternate between parallel and anti-parallel orientations and G
residues in adjacent layers alternate between the synand anticonformations. A similar arrangement had also
been found for an intra-molecular quadruplex formed by the G 4 T 4 -repeat sequence from Oxytricha nova.
Moreover, by use of X-ray crystallography it was found that the DNA sequences TG 4 T (4; Naform),
TAGGGTTAGGGT (2; Kform) and the above 22 mer AG 3 (T 2 AG 3 ) 3 (intramolecular; Kform, Figure
2.35) all adopted quadruplexes with parallel orientations of strands.^40 Most of the deoxyguanosine sugars
exhibit the C2-endopucker. However, in contrast to the above parallel/anti-parallel-type quadruplex, the
glycosylic bonds in the four-stranded motifs with parallel orientation of strands adopt exclusively the anti
conformation. The local G-quartet rise is about 3.13 Å and the four strands writhe in a right-handed fashion
with an average twist of around 30° between adjacent layers. Therefore, the G-rich quadruplex is extensively
stabilised by –stacking interactions between layers of guanines. Potassium ions are trapped in the core
between stacked G-quartets, spaced at ca.2.7 Å from each of a total of eight O-6 carbonyl groups (Figure 9.2).
A major difference between the four-stranded motifs formed by G- and C-rich sequences is that the
former are stable at neutral pH, whereas the latter require protonation of half the cytosine residues and
hence are stable only at lower values of pH. Maurice Guéron’s laboratory provided the initial structure of
the C-rich motif a decade ago, determined by solution NMR methods.^41 They termed it intercalation or
i-motiffor the peculiar four-stranded arrangement involving two parallel intercalating duplexes, each held
together by CCbase pairs (Figure 2.36). The two duplexes are intercalated with opposite polarity, and a
54 Chapter 2
Figure 2.36 (a) The i-motif adopted by four molecules of d(C) 4 (PDB:190D). Atoms are coloured green, red, blue
and magenta for carbon, oxygen, nitrogen and phosphorus, respectively. Positions of phosphorus atoms
from the two intercalated CC-paired duplexes are traced by orange (5-ends at the top and 3-ends at
the bottom) and grey (5-ends at the bottom and 3-ends at the top) ribbons, respectively, to highlight
their anti-parallel relative orientation. The absence of significant overlap between cytosine planes from
adjacent hemiprotonated base pairs and two wide grooves and two narrow grooves with van der Waals
contacts between anti-parallel strands from two duplexes across the latter grooves are hallmarks of the
i-motif. (b) Schematic line diagram of the i-motif, illustrating the formation of intercalated parallel-
stranded CC-paired duplexes with opposite polarities