Structures and properties of multi-stranded nucleic acids

Nucleic acids exist in a number of structural states that may comprise one to four strands. Common features involve base-stacking and pairing of complementary bases via H-bonded interactions, although a wide variety of pairing motifs are found in higher-order structures. Another property is the marked flexibility of nucleic acids reflected in their solution behaviour, thermodynamic stability and interactions with proteins and small ligand molecules. The electrostatic properties of a nucleic acid and its ability to pack into high-order structure(s) are largely determined by the anionic phosphodiester backbone. This feature is particularly evident for triple-helical assemblies, where there is close proximity between phosphates and intrinsic thermodynamic stability is strongly influenced by ionic strength. Structural stabilisation of parallel triplexes can also be modulated by the presence of positive charge, achieved through either N3-protonation of cytosine bases or the deliberate incorporation of charged residues into the third strand. Salt effects are also pronounced in four-stranded structures such as the i-motif and G-tetraplex ("quadruplex") assemblies; indeed, different structures are produced for the latter depending on the nature of the associated cation. High-order nucleic acid structures are currently a focus of intense interest in antisense and antigene strategies toward novel chemotherapeutic agents. An understanding of both their structural details and solution properties is essential for a rational approach to DNA-targeted drug design.