THE THEORETICAL LIMITS OF DNA-SEQUENCE DISCRIMINATION BY LINKED POLYAMIDES

Linked polyamides bind in the minor groove of double-stranded DNA in a partially sequence specific manner. This report analyzes the theoreti cal limits of DNA sequence discrimination by linked polyamides compose d of two to four different types of heterocyclic rings, determining (i ) the optimal choice of base-binding specificity for each ring and (ii ) the optimal design for a polyamide composed of these rings to target a given DNA sequence and designed to maximize the fraction of the tot al polyamide binding to the specified target sequence relative to all other sequences. The results show that, fortuitously, polyamides compo sed of pyrrole, a naturally occurring G-excluding element, and imidazo le, a rationally designed G-favoring element, have features similar to the theoretical optimum design for polyamides composed of two differe nt rings. The results also show that, in polyamides composed of two or three types of heterocyclic rings, choosing a nonspecific ''placehold er'' ring, which binds equally strongly to each of the four bases, alo ng with one or two base-specific rings will often enhance sequence spe cificity over a polyamide composed entirely of base-specific rings.