Recognition of ten base pairs of DNA by head-to-head hairpin dimers.
Hairpin polyamides coupled head-to head with alkyl linkers of varying lengths were synthesized, and their DNA binding properties were determined. The DNA binding affinities of six-ring hairpin dimers Im-Im-Py-(R)[Im-Im-Py-(R)(HNCO(CH))(n)(CO)gamma-Py-Py-Py-beta-Dp](NH)gamma-Im-Py-Py-beta-Dp (1-4) (where n = 1-4) for their 10-bp, 11-bp, and 12-bp match sites 5'-TGGCATACCA-3', 5'-TGGCATTACCA-3', and 5'-TGGCATATACCA-3' were determined by quantitative DNase I footprint titrations. The most selective dimer Im-Im-Py-(R)[Im-Im-Py-(R)(HNCO(CH)(2))(2)(CO)gamma-Py-Py-Py-beta-Dp](NH)gamma-Im-Py-Py-beta-Dp (2) binds the 10-bp site match site with an equilibrium association constant of K(a) = 7.5 x 10(10) M(-1) and displays 25- and 140-fold selectivity over the 11-bp and 12-bp match sites, respectively. The affinity toward single base pair mismatched sequences is 4- to 8-fold lower if one hairpin module of the dimer is affected, but close to 200-fold lower if both hairpin modules face a single mismatch base pair. The head-to-head hairpin dimer motif expands the binding site size of DNA sequences targetable with polyamides.
Weyermann
Philipp
P
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Dervan
Peter B
PB
D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA; C096654:N-methylpyrrole; C018100:1-methylimidazole