Peptide bis-intercalator binds DNA via threading mode with sequence specific contacts in the major groove.
BACKGROUND
We previously described a general class of DNA polyintercalators in which 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) intercalating units are connected via peptide linkers, resulting in the first known tetrakis- and octakis-intercalators. We showed further that changes in the composition of the peptide tether result in novel DNA binding site specificities. We now examine in detail the DNA binding mode and sequence specific recognition of Compound 1, an NDI bis-intercalator containing the peptide linker gly-gly-gly-lys.


RESULTS
1H-NMR structural studies of Compound 1 bound to d(CGGTACCG)(2) confirmed a threading mode of intercalation, with four base pairs between the diimide units. The NMR data, combined with DNAse I footprinting of several analogs, suggest that specificity depends on a combination of steric and electrostatic contacts by the peptide linker in the floor of the major groove.


CONCLUSIONS
In view of the modular nature and facile synthesis of our NDI-based polyintercalators, such structural knowledge can be used to improve or alter the specificity of the compounds and design longer polyintercalators that recognize correspondingly longer DNA sequences with alternating access to both DNA grooves.
Guelev
V
V
Department of Chemistry and Biochemistry, The University of Texas at Austin, 78722, USA.
Lee
J
J
Ward
J
J
Sorey
S
S
Hoffman
D W
DW
Iverson
B L
BL
D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000502:physiology; D017931:DNA Primers / Q000737:chemistry*; D007094:Imides / Q000737:chemistry*; D007364:Intercalating Agents / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D023302:Protein Footprinting; D055672:Static Electricity
C429685:1,4,5,8-naphthalenetetracarboxylic diimide; D017931:DNA Primers; D007094:Imides; D007364:Intercalating Agents; D009281:Naphthalenes; D010455:Peptides