Cation-Driven Conformational Switches

The possibility of cation-induced changes in G-quadruplex structure has formed the basis for the hypothesis that DNA G-quadruplexes might function as molecular switches in vAo. In this section we review experiments related to reports of cation-driven conformational changes by G-quadruplexes. While this proposal is certainly related to the cation-dependent polymorphisms described in Section 4.6, the results presented in this section are more focused on G-quadruplex sequences and transitions that have been proposed as possible cation-dependent molecular switches, particularly those sequences derived from telomere DNA sequences. 

There is also evidence for the formation of simpler, hairpin structures stabilized by GG base pairs, rather than G-quartets, in oligonucleotides derived from the O. nova telomere repeat, d(T4G4)2 and dTg(T4G4)2, in the presence of 

10-50 mM NaCl. In the presence of 150mM KCl, these sequences are converted to parallel, tetramolecular quadruplexes. These GG-based hairpins 

Thomas and co-workers used Raman spectroscopy to generate a phase diagram of antiparallel and parallel G-quadruplex structures as controlled by concentrations of Na and K ions. Both alkali ions facilitate the formation of an antiparallel diagonal-loop G-quadruplex by four units of the telomere repeat sequence of O. nova, d(T4G4)4, at low concentrations. An extended, parallel-stranded tetramolecular G-quadruplex is formed at higher cation concentrations. However, K is more effective than Na in inducing the parallel strand association. The midpoints of the Na and K concentrations required for the structural transition are 225 and 65 mM, respectively.  

As mentioned above, the switching between antiparallel and parallel G-quadruplexes can also be driven by divalent cations. A continuous structural transition from an antiparallel to a parallel G-quadruplex structure adopted by d(G4T4G4), which spontaneously assembles into G-wires, was observed with Ca titration in the presence of 100 mM NaCl. The structural transition was completed by adding 20 mM Ca , and d(G4T4G4) has been shown to fold into a parallel G-quadruplex in the presence of Ca ions alone. As little as a 1 mM concentration of divalent cations was sufficient to destabilize the bimolecular, antiparallel G-quadruplex formed by d(G4T4G4). Thus, divalent cations might also prove to be a powerful tool for regulating G-quadruplex structures.  

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