TY - JOUR
T1 - Heterocyclic diamidine interactions at AT base Pairs in the DNA minor groove
T2 - Effects of heterocycle differences, DNA AT sequence and length
AU - Liu, Yang
AU - Collar, Catharine J.
AU - Kumar, Arvind
AU - Stephens, Chad E.
AU - Boykin, David W.
AU - Wilson, W. David
PY - 2008/9/18
Y1 - 2008/9/18
N2 - Given the increasing significance of diamidines as DNA-targeted therapeutics and biotechnology reagents, it is important to establish the variations in thermodynamic quantities that characterize the interactions of closely related compounds to different sequence AT binding sites. In this study, an array of methods including biosensor-surface plasmon resonance (SPR), isothermal titration microcalorimetry (ITC), circular dichroism (CD), thermal melting (Tm) and molecular modeling have been used to characterize the binding of dicationic diamidines related to DB75 (amidine-phenyl-furan-phenyl-amidine) with alternating and nonalternating AT sequences. Conversion of the central furan of DB75 to other similar groups, such as thiophene or selenophene, can yield compounds with increased affinity and sequence binding selectivity for the minor groove. Calorimetric measurements revealed that the thermodynamic parameters (ΔG, ΔH, ΔS) that drive diamidine binding to alternating and nonalternating oligomers can be quite different and depend on both DNA sequence and length. Small changes in a compound can have major effects on DNA interactions. By choosing an appropriate central group it is possible to "tune" the shape of the molecule to match DNA for enhanced affinity and sequence recognition.
AB - Given the increasing significance of diamidines as DNA-targeted therapeutics and biotechnology reagents, it is important to establish the variations in thermodynamic quantities that characterize the interactions of closely related compounds to different sequence AT binding sites. In this study, an array of methods including biosensor-surface plasmon resonance (SPR), isothermal titration microcalorimetry (ITC), circular dichroism (CD), thermal melting (Tm) and molecular modeling have been used to characterize the binding of dicationic diamidines related to DB75 (amidine-phenyl-furan-phenyl-amidine) with alternating and nonalternating AT sequences. Conversion of the central furan of DB75 to other similar groups, such as thiophene or selenophene, can yield compounds with increased affinity and sequence binding selectivity for the minor groove. Calorimetric measurements revealed that the thermodynamic parameters (ΔG, ΔH, ΔS) that drive diamidine binding to alternating and nonalternating oligomers can be quite different and depend on both DNA sequence and length. Small changes in a compound can have major effects on DNA interactions. By choosing an appropriate central group it is possible to "tune" the shape of the molecule to match DNA for enhanced affinity and sequence recognition.
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U2 - 10.1021/jp804048c
DO - 10.1021/jp804048c
M3 - Article
C2 - 18717551
AN - SCOPUS:53049105244
SN - 1520-6106
VL - 112
SP - 11809
EP - 11818
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 37
ER -