Chemistry Reference
In-Depth Information
antiparallel. The other was a head-to-head hairpin quadruplex with one adjacent
strand parallel and the other antiparallel.
95
The second type of loop joins opposite
antiparallel G-strands by spanning the diagonal of the outer G-quartet (Figure
3.3b). Such loops usually consist of three or more residues. Diagonal loops were
observed, for example, in the structure formed by the
Oxytricha nova
telomeric
sequence d(G
4
T
4
G
4
).
96 - 100
Adjacent parallel strands can be connected by a double-
chain reversal loop that links the 3
- end of the
other (Figure 3.3c). This loop arrangement gives a G-quadruplex a propeller type
topology,
101
with loops that can consist of a single or several residues.
102 - 104
A double -
chain reversal loop has been found both in crystal and solution-state structures for
G-quadruplexes adopted by human telomeric DNA sequences, and more recently
in a number of nontelomeric quadruplexes (see below). Residues in all three loop
orientations have been shown to contribute to the stability of G-quadruplex struc-
tures though base-pairing and stacking over the neighbouring G-quartets.
95,105 - 114
It
is noteworthy that loops can adopt diverse structures beyond the basic classifi cation
mentioned above, which can be targeted by small molecule ligands.
′
-end of a given G-tract with the 5
′
3.2 Cation Coordination and Stability of G - Quadruplexes
Early NMR studies of alkali metal ion specifi city suggested that 5
- GMP formed
self-ordered structures consisting of stacked G-quartets in the presence of K
+
, Na
+
and Rb
+
, but not Li
+
or Cs
+
.
115
The fi rst experimental evidence for direct coordina-
tion of dehydrated cations between G-quartets was provided by the observation of
broadening and shielding of the
23
Na resonance in solutions of 5
′
- GMP.
116,117
K
+
and
Na
+
ions are the most extensively characterized cations with respect to their ability
to stabilize G-quadruplex structures.
118 - 122
A list of other cations that have been
shown to promote G-quadruplex formation includes the monovalent cations Rb
+
,
Cs
+
,
123,124
NH
4
+
125,126
and Tl
+
100,127 - 129
as well as the divalent cations Sr
2+
,
124,130 - 133
Ba
2+
,
134,135
and Pb
2+
.
125,136 - 138
In general, low divalent cation concentrations initially
stabilize G - quadruplexes,
139
while increasing concentrations eventually become
destabilizing. Mn
2+
and europium cations that stabilize G-quadruplex have been
localized in the grooves.
140,141
Studies of 8 - bromoguanosine gel melting - transition
temperatures indicated the following relative G-quartet stabilizing propensities of
divalent cations: Sr
2+
′
Mg
2+
. Davis and coworkers have shown that, in
the presence of Pb
2+
, lipophilic guanine analogues can associate to form quadruplex-
like structures in organic solvents.
142
These results affi rmed earlier studies that Pb
2+
induces a more stable and compact structure compared to K
+
, which is evident from
the comparison of cation-O6 bond lengths, O6-O6 diagonal distances and inter-
quartet separation.
136
Studies by Hardin and coworkers have shown that Mg
2+
and
Ca
2+
ions stabilize the tetramolecular parallel-stranded G-quadruplexes formed by
the sequences d(CGCG
3
GCG) and d(TATG
3
ATA) more than monovalent alkali
cations.
143,144
A CD spectroscopic study by Sugimoto and coworkers has shown
that the bimolecular G-quadruplex d[(G
4
T
4
G
4
)
2
] formed in the presence of NaCl is
actually destabilized by only 1 mM concentrations of Mg
2+
, Ca
2+
, Mn
2+
, Co
2+
, or
B a
2+
Ca
2+
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