The stability of intramolecular DNA G-quadruplexes compared with other macromolecules

DNA quadruplexes are often conceived as very stable structures. However, most of the free energy of stabilization derives from specific ion binding via inner sphere coordination of the GO6 of the guanine residues comprising the basic quartet. When compared with other nucleic acid structures such as DNA or RNA duplexes and hairpins, or proteins of the same number of atoms, metal-coordinated intramolecular quadruplexes are found to be of comparable or lower thermodynamic stability under similar solution conditions. Furthermore, intramolecular quadruplexes are actually less stable kinetically, than DNA duplexes or hairpins of the same size. Although the literature is incomplete, it is clear that polyelectrolyte ion effects, the influence of solvation and steric crowding on stability are qualitatively different between intramolecular quadruplexes and DNA duplexes. For example, decreasing water activity destabilizes DNA duplexes, whereas quadruplexes are stabilized. The variety of folded conformations accessible to a single sequence further implies strong sensitivity of the conformational ensemble to the solution conditions, compared with DNA duplexes or small single domain proteins. These considerations may have relevance to the conditions prevailing inside cell nuclei and therefore the structures that potentially might form in vivo.