Stability and structure of model DNA triplexes and quadruplexes and their interactions with small ligands

This review focuses on the structural and thermodynamic characterization of model DNA triplex and quadruplex structures, taking into account effects of stoichiometry and sequence. Methods such as gel electrophoresis, UV melting, and scanning calorimetry, and the results thereof, are described for determination of the thermodynamic stability of such systems. Three classes of triplexes are considered based on the composition of the third strand, while quadruplex systems are limited to those based on the guanine quartet. X-ray crystallography and high resolution NMR studies are also described for these two classes of unusual structures. Ligand binding to triplexes and quadruplexes is also reviewed, with emphasis on specific molecular recognition. The availability of three-dimensional structures for triplex and quadruplex species sets the stage for structure-based development of ligands capable of binding to them specifically. To this end, we consider the application of DOCK, a program for the discovery of small molecules that can recognize macromolecular structures, to the problem of recognizing folded quadruplex structures. Such studies may ultimately lead to pharmaceutically active compounds.