The interaction of intercalators and groove-binding agents with DNA triple-helical structures: the influence of ligand structure, DNA backbone modifications and sequence.
The effects of ligand structure and properties, DNA backbone modifications and DNA sequence on the interaction of a variety of well-known groove-binding agents and intercalators with DNA duplexes and triplexes have been evaluated by thermal melting experiments and molecular modeling. Both methylphosphonate 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 suggest that the large intercalating ring system 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.(T4C)3T4) causes very significant decreases in observed Tm 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 intercalators, the large difference observed between the pure AT and the mixed sequence triplexes suggest that they may also have differences in structure and properties.
Wilson
W D
WD
Department of Chemistry, Georgia State University, Atlanta 30303.
Mizan
S
S
Tanious
F A
FA
Yao
S
S
Zon
G
G
D001483:Base Sequence; D001600:Berberine Alkaloids / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D007364:Intercalating Agents / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D011796:Quinacrine / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D001600:Berberine Alkaloids; D007364:Intercalating Agents; D008024:Ligands; C000666:coralyne; D004247:DNA; D011796:Quinacrine