AN ANALYSIS OF A CLASS OF DNA-SEQUENCE READING MOLECULES

Linked polyamides are a class of designed molecules that bind in the m inor groove of double-stranded DNA in a partially sequence-specific ma nner but have limited sequence discriminatory abilities. This suggests a need for design alternatives to create molecules with enhanced sequ ence specificity. In this report we present formal proofs of the theor etical limits of the DNA sequence specificity of hypothetical sequence reading molecules as a function of their base recognition properties and sequence content and length of their target sequence. We prove tha t molecules containing nonspecific readers at critical positions withi n the molecule may have enhanced sequence specificity over molecules c omposed entirely of base specific reading elements. We also determine optimal patterns of base recognition for molecules in order to optimiz e their target sequence specificity. We also examine the effect of the length of a polyamide (i.e., the number of base pairs it binds) on it s sequence discriminatory ability and determine necessary concentratio n dependent constraints on the binding free energies in order for long er polyamides to have greater sequence specificity than shorter ones. We show that unless the discriminatory ability of a ring for its prefe rred base is very strong, longer polyamides do not necessarily have gr eater sequence specificity over shorter ones when compared at the same molar concentration.