The interaction of intercalators and groove‐binding agents with DNA triple‐helical structures: The influence of ligand structure, DNA backbone modifications and sequence

Abstract

The effect of ligand structure and properties, DNA backbone modifications and DNA sequence on the interaction of a variety of well‐known groove‐binding agents and intercalates with DNA duplexes and triplexes have been evaluated by thermal melting experiments and molecular modeling. Both methyphosphonate and phosphorothioate substitutions generally destabilize DNA duplexes and triplexes. Modified duplexes can be strongly stabilized by both groove‐binding agents and intercalators whereas triplexes are primarily stabilized by intercalators. Of the compounds tested, the intercalators coralyne and quinacrine provide the largest stabilization of the triplex dT₁₉ · dA₁₉ · dT₁₉. Molecular modeling studies suggests that the large intercalating ring systems of coralyne stacks well with the triplex bases whereas the alkylamino side chain of quinacrine fits snugly into the remaining space of the major groove of dT₁₉ · dA₁₉ · dT₁₉ triplex and forms extensive van der Waals contacts with the thymine methyl groups that line the groove. Converting some of the T · A · T base triples to C⁺ · G · C (e.g. dT₁₉ · dA₁₉ · dT₁₉ to d(T₄C⁺)₃T₄ · d(A₄G)₃A₄) causes very significant decreases in observed T_m increases for compounds such as quinacrine and coralyne. Although removal of thymine methyl groups and addition of positive charge on substitution of C⁺ · G · C for T · A · T should reduce binding of cationic intercalates, the large difference observed between the pure AT and the mixed sequence triplexes suggest that they may also have differences in structure and properties.