Influence of the permutation of imidazole and pyrrole moieties on the binding affinity of polyamides to their cognate and non-cognate DNA sequences

ORGN 361

Karen Buchmueller1, Horick Sarah1, Peter Uthe1, Andrew Staples1, Opperman-Pacheco Kimberly2, Binh Nguyen3, David Wilson3, and Moses Lee4. (1) Chemistry, Furman University, 3300 Poinsett Highway, Greenville, SC 29613, (2) Chemistry, University of Northern Colorado, Greeley, CO 80639, (3) Department of Chemistry, Georgia State University, 50 Decatur Street, Atlanta, GA 30303, (4) Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, SC 29613
Distamycin binds preferentially as an anti-parallel stacked dimer in the minor groove of AAATTT. In this binding motif, a side-by-side Py/Py pairing recognizes A/T or T/A, Py/Im recognizes C/G, Im/Py recognizes G/C, and Im/Im recognizes a T/G or G/T mismatched base pair. Im/Im also binds to G/C or C/G, but with lower affinity. Stacked polyamides containing Py/Py or Im/Im pairings could thus recognize multiple cognate sequences. In this study, the interaction of a selected series of triamides with all possible cognate and several non-cognate DNA sequences were investigated using a combination of surface plasmon resonance, thermal DNA melt, circular dichroism, and competitive dialysis. The results from our studies reveal that the binding constant of formamido-Im-Py-Im to its cognate CGCG sequence is almost a thousand-fold larger than the binding of formamido-Py-Im-Im to its CCGG cognate sequence. Details of the biophysical studies and a discussion of the results and observations will be presented.