STRUCTURAL CHARACTERIZATION OF SIDE-BY-SIDE BINDING FOR A CROSS-LINKED LEXITROPSIN DIMER DESIGNED TO TARGET G-CENTER-DOT-C BASE-PAIRS IN THE DNA MINOR-GROOVE

Recent efforts at designing lexitropsins for sequence-specific recogni tion in the minor groove of DNA have focused on utilizing the 2:1 liga nd-DNA interaction models where two ligand molecules may simultaneousl y bind as side-by-side antiparallel dimers, Covalent linkage of two le xitropsin molecules, each a pyrrole-pyrrole-imidazole tripeptide, is s hown to provide a further improvement in the binding affinity and spec ificity for a designated duplex sequence containing G . C base pairs. Evidence for bivalent sequence- and strand-specific binding of the dim er and structural characterization of its complex with d(CGAACATGTTCG) (2) using NMR and restrained molecular modeling/dynamics methods are d iscussed. These results suggest that selectivity of lexitropsins for D NA sequences may arise primarily from an extended array of specific in termolecular hydrogen bonds at the floor of the minor groove in DNA.