DNA minor-groove recognition by 3-methylthiophene/pyrrole pair.
Hairpin polyamides are synthetic oligomers, which fold and bind to specific DNA sequences in a programmable manner. Internal side-by-side pairings of the aromatic amino acid residues 1-methyl-1H-pyrrole (Py), 1-methyl-1H-imidazole (Im), and 3-hydroxy-1-methyl-1H-pyrrole (Hp) confer the ability to distinguish between all four Watson-Crick base pairs in the minor groove of B-form DNA. In a broad search to expand the heterocycle repertoire, we found that when 3-methylthiophene (Tn), which presents a S-atom to the minor groove, is paired with Py, it exhibits a modest threefold specificity for TA>AT presumably by shape-selective recognition. In this study, we explore the scope and limitations of this lead by incorporating multiple Tn residues within a single hairpin polyamide. It was found that hairpin polyamides containing more that one Tn/Py pair exhibit lowered affinities and specificities for their match sites. It appears that little deviation is permissible from the parent five-membered ring 1-methyl-1H-pyrrole-2-carboxamide scaffold for DNA recognition.
Doss
Raymond M
RM
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Marques
Michael A
MA
Foister
Shane
S
Dervan
Peter B
PB
D024322:Amino Acids, Aromatic / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism*
D024322:Amino Acids, Aromatic; D011758:Pyrroles; D013876:Thiophenes; D004247:DNA