Structural Characterization of Side-by-Side Binding for a Cross-Linked Lexitropsin Dimer Designed to Target G • C Base Pairs in the DNA Minor Groove

摘要

Recent efforts at designing lexitropsins for sequence-specific recognition in the minor groove of DNA have focused on utilizing the 2:1 ligand-DNA interaction models where two ligand molecules may simultaneously bind as side-by-side antiparallel dimers. Covalent linkage of two lexitropsin molecules, each a pyrrole-pyrrole-imidazole tripeptide, is shown to provide a further improvement in the binding affinity and specificity for a designated duplex sequence containing G·C base pairs. Evidence for bivalent sequence- and strand-specific binding of the dimer and structural characterization of its complex with d(CGAACATGTTCG)_2 using NMR and restrained molecular modeling/dynamics methods are discussed. These results suggest that selectivity of lexitropsins for DNA sequences may arise primarily from an extended array of specific intermolecular hydrogen bonds at the floor of the minor groove in DNA.