Electronic energy changes associated with Guanine quadruplex formation: an investigation at the atomic level

Guanine quadruplexes have received a lot of attention due to their possible role as therapeutic agents. Specifically, it is the ability of these quadruplex structures to inhibit telomerase, an enzyme found to be highly active in a large percentage of tumor cells and thought to confer immortality upon these cells. However, although a great deal of research has focused on enhancing the formation of these structures and their anticancer activity, many questions remain about the quadruplex structures themselves. The current study probes the nature of these quadruplex structures at the atomic level. Individual atomic energies have been computed for the quadruplex structure and compared to the atomic energies of the unfolded telomere to determine the energetic consequences of quadruplex formation. The results suggest several interesting trends, most notably that the guanine quartets exhibit an alternating pattern of stabilization and destabilization and these regions actually overlap in the intact quadruplex. In addition, the TTA loop segments are largely stabilized, whereas the atoms in the sugar-phosphate backbone exhibit mostly minor changes going from the unfolded to folded state. Inclusion of additional sodium cations in the central core of the quadruplex has a minimal effect on the atomic energies except for the atoms that are closest to the cations, which are largely stabilized in the presence of these ions.