DNA microstructure influences selective binding of small molecules designed to target mixed-site DNA sequences.
Specific targeting of protein–nucleic acid interactions is an area of current interest, for example, in the regulation of gene-expression. Most transcription factor proteins bind in the DNA major groove; however, we are interested in an approach using small molecules to target the minor groove to control expression by an allosteric mechanism. In an effort to broaden sequence recognition of DNA-targeted-small-molecules to include both A·T and G·C base pairs, we recently discovered that the heterocyclic diamidine, DB2277, forms a strong monomer complex with a DNA sequence containing 5΄-AAAGTTT-3΄. Competition mass spectrometry and surface plasmon resonance identified new monomer complexes, as well as unexpected binding of two DB2277 with certain sequences. Inherent microstructural differences within the experimental DNAs were identified through computational analyses to understand the molecular basis for recognition. These findings emphasize the critical nature of the DNA minor groove microstructure for sequence-specific recognition and offer new avenues to design synthetic small molecules for effective regulation of gene-expression.
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
Sarah
S
Laughlin-Toth
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
E Kathleen
EK
Carter
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
Ivaylo
I
Ivanov
Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA
W David
WD
Wilson
D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005813:Genes, Synthetic; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D021241:Spectrometry, Mass, Electrospray Ionization; D020349:Surface Plasmon Resonance
D004247:DNA