Theoretical limits of DNA sequence discrimination of polyamides

Linked polyamides bind in the minor groove of double-stranded DNA in a partially sequence-specific manner but have limited sequence discriminatory abilities, suggesting a need for design alternatives to create molecules with enhanced sequence selectivity. We present an analysis of the theoretical limits of the DNA sequence selectivity of hypothetical sequence reading molecules as a function of their base recognition properties and sequence content of their target sequence. The analysis shows the nonobvious result that molecules containing nonspecific readers at critical positions within the molecule may have enhanced sequence selectivity over molecules composed entirely of base specific reading elements. We apply this result to determine optimal patterns of base recognition for molecules in order to optimize their target sequence selectivity. We also examine the effect of the length of a polyamide (i.e. the number of base pairs it binds) on its sequence discriminatory ability and determine necessary concentration dependent constraints on the binding free energies in order for longer polyamides to have greater sequence specificity than shorter ones.