Thermodynamic and Structural Basis of Selectivity in the Binding of Tetrapentylammonium to G-Quadruplexes

G-quadruplexes are an important class of noncanonical DNA structures that form from contiguous guanine repeats (G-tracts) and are implicated in the regulation of genomic events. They are polymorphic in nature and, depending upon the orientation of their G-tracts, may fold into a parallel, antiparallel, or hybrid topology. We previously found that tetraalkylammonium ions ([H(CH2)n]4N+), despite their simplicity, bind to the parallel c-MYC G-quadruplex but not to the antiparallel human telomeric Tel22 G-quadruplex or to duplex DNA. Within a homologous series of these structural minimalists, tetrapentylammonium (TPeA+) exhibits the highest affinity for the c-MYC G-quadruplex. The structure of the resulting stable complex has been solved by NMR. To discover the origins of that selectivity, we examine here nine biologically relevant G-quadruplexes, which differ in sequence and topology, for the effect of TPeA+ on their melting temperatures, taken as a measure of thermal stability. The stoichiometry of binding, the binding constant, and the binding enthalpy were determined for each G-quadruplex, and those thermodynamic parameters were related to the structural features of the G-quadruplexes. Binding of TPeA+ to all nine DNA sequences is driven by hydrophobic interactions, as indicated by the entropy-driven nature of the binding and by self-evident Coulombic interactions between the positively charged ligand and polyanionic DNA. Selectivity is seen in binding constants that range from 40,500 M–1 for c-MYC to nil for Tel22. Comparisons with structure indicate that binding is facilitated by unobstructed access to the receiving G-quartet and favorable interactions with the flanking sequence. These results expand our understanding of the forces that direct the targeting of DNA, with implications for the development of tetraalkylammonium ions and their derivatives as a novel family of topology-selective G-quadruplex-binding agents.