Characterization of a novel DNA minor-groove complex.
Many dicationic amidine compounds bind in the DNA minor groove and have excellent biological activity against a range of infectious diseases. Para-substituted aromatic diamidines such as furamidine, which is currently being tested against trypanosomiasis in humans, and berenil, which is used in animals, are typical examples of this class. Recently, a meta-substituted diamidine, CGP 40215A, has been found to have excellent antitrypanosomal activity. The compound has a linear, conjugated linking group that can be protonated under physiological conditions when the compound interacts with DNA. Structural and molecular dynamics analysis of the DNA complex indicated an unusual AT-specific complex that involved water-mediated H-bonds between one amidine of the compound and DNA bases at the floor of the minor groove. To investigate this unique system in more detail DNase I footprinting, surface plasmon resonance biosensor techniques, linear dichroism, circular dichroism, ultraviolet-visible spectroscopy, and additional molecular dynamics simulations have been conducted. Spectrophotometric titrations of CGP 40215A binding to poly(dAT)(2) have characteristics of DNA-binding-induced spectral changes as well as effects due to binding-induced protonation of the compound linker. Both footprinting and surface plasmon resonance results show that this compound has a high affinity for AT-rich sequences of DNA but very weak binding to GC sequences. The dissociation kinetics of the CGP 40215A-DNA complex are much slower than with similar diamidines such as berenil. The linear dichroism results support a minor-groove complex for the compound in AT DNA sequences. Molecular dynamics studies complement the structural analysis and provide a clear picture of the importance of water in mediating the dynamic interactions between the ligand and the DNA bases in the minor groove.
Nguyen
Binh
B
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
Hamelberg
Donald
D
Bailly
Christian
C
Colson
Pierre
P
Stanek
Jaroslav
J
Brun
Reto
R
Neidle
Stephen
S
Wilson
W David
WD
D001483:Base Sequence; D001665:Binding Sites; D003198:Computer Simulation; D007700:Kinetics; D046911:Macromolecular Substances; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011067:Poly dA-dT / Q000737:chemistry*; D011089:Polydeoxyribonucleotides / Q000737:chemistry*; D012370:Robenidine / Q000031:analogs & derivatives* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
D046911:Macromolecular Substances; D011089:Polydeoxyribonucleotides; D014867:Water; C102850:bis((3-(aminoiminomethyl)phenyl)methylene)carbonimidic dihydrazide trihydrochloride; D011067:Poly dA-dT; C019530:poly(dC-dG); D012370:Robenidine