Molecular recognition between oligopeptides and nucleic acids: DNA sequence specificity and binding properties of thiazole-lexitropsins incorporating the concepts of base site acceptance and avoidance.

The DNA binding and sequence specificity of a group of six novel thiazole containing lexitropsins related to the natural anti-tumor antibiotic distamycin have been examined by complementary strand MPE footprinting on two restriction fragments of pBR322 DNA. These lexitropsins comprise two groups in which the hetero atom of the thiazole moiety directed inwards to the floor of the minor groove is respectively nitrogen or sulfur. All of the new lexitropsins bind to DNAs in the minor groove with Kapp comparable with distamycin. The group of lexitropsins bearing nitrogen directed towards the DNA display comparable binding to poly(dA-dT) and to native DNAs, and complementary strand footprinting reveals their ability to accept and bind to mixed AT-GC sequences. The GC recognizing property plausibly arises from the hydrogen bonding between the thiazole nitrogen and G-2-NH2 based on precedents. In contrast the group of lexitropsins bearing sulfur directed towards the floor of the minor groove of DNA exhibit strict preference for AT sequences and are even more discriminating than distamycin. The latter agents, in common with the first group, bind firmly in the minor groove and with a binding site size of either 4 +/- 1 or 5 +/- 1 base pairs indicating intimate contact of all parts of the ligand. Therefore the property of GC site avoidance of these particular thiazole-lexitropsins is attributed to clash between the sterically more demanding sulfur and G-2NH2 groups.