TY - JOUR
T1 - DNA Minor Groove Induced Dimerization of Heterocyclic Cations
T2 - Compound Structure, Binding Affinity, and Specificity for a TTAA Site
AU - Munde, Manoj
AU - Kumar, Arvind
AU - Nhili, Raja
AU - Depauw, Sabine
AU - David-Cordonnier, Marie Hélène
AU - Ismail, Mohamed A.
AU - Stephens, Chad E.
AU - Farahat, Abdelbasset A.
AU - Batista-Parra, Adalgisa
AU - Boykin, David W.
AU - Wilson, W. David
N1 - Funding Information:
This research was supported by National Institutes of Health grants AI064200 and GM61587 (W.D.W. and D.W.B.). Biacore instruments were purchased with partial support from the Georgia Research Alliance. We acknowledge the Ligue Nationale contre le Cancer (Comité du Nord) and the Institut pour la Recherche sur le Cancer de Lille for grants to M.-H.D.-C., the Fonds européen de développement régional (FEDER, European Community) and the Région Nord-Pas de Calais for a grant and a fellowship to S.D., the CHRU de Lille and the Conseil Régional Nord-Pas de Calais for a Ph.D. fellowship to R.N., and the Institut de Médecine Prédictive et de Recherche Thérapeutique—IFR114 for access to the Molecular Dynamics STORM 860 equipment.
PY - 2010/10/8
Y1 - 2010/10/8
N2 - With the increasing number and variations of genome sequences available, control of gene expression with synthetic, cell-permeable molecules is within reach. The variety of sequence-specific binding agents is, however, still quite limited. Many minor groove binding agents selectivity recognize AT over GC sequences but have less ability to distinguish among different AT sequences. The goal with this article is to develop compounds that can bind selectively to different AT sequences. A number of studies indicate that AATT and TTAA sequences have significantly different physical and interaction properties and different requirements for minor groove recognition. Although it has been difficult to get minor groove binding at TTAA, DB293, a phenyl-furan-benzimidazole diamidine, was found to bind as a strong, cooperative dimer at TTAA but with no selectivity over AATT. In order to improve selectivity, we made modifications to each unit of DB293. Binding affinities and stoichiometries obtained from biosensor-surface plasmon resonance experiments show that DB1003, a furan-furan-benzimidazole diamidine, binds strongly to TTAA as a dimer and has selectivity (KTTAA/KAATT=6). CD and DNase I footprinting studies confirmed the preference of this compound for TTAA. In summary, (i) a favorable stacking surface provided by the pi system, (ii) H-bond donors to interact with TA base pairs at the floor of the groove provided by a benzimidazole (or indole) -NH and amidines, and (iii) appropriate curvature of the dimer complex to match the curvature of the minor groove play important roles in differentiating the TTAA and AATT minor grooves.
AB - With the increasing number and variations of genome sequences available, control of gene expression with synthetic, cell-permeable molecules is within reach. The variety of sequence-specific binding agents is, however, still quite limited. Many minor groove binding agents selectivity recognize AT over GC sequences but have less ability to distinguish among different AT sequences. The goal with this article is to develop compounds that can bind selectively to different AT sequences. A number of studies indicate that AATT and TTAA sequences have significantly different physical and interaction properties and different requirements for minor groove recognition. Although it has been difficult to get minor groove binding at TTAA, DB293, a phenyl-furan-benzimidazole diamidine, was found to bind as a strong, cooperative dimer at TTAA but with no selectivity over AATT. In order to improve selectivity, we made modifications to each unit of DB293. Binding affinities and stoichiometries obtained from biosensor-surface plasmon resonance experiments show that DB1003, a furan-furan-benzimidazole diamidine, binds strongly to TTAA as a dimer and has selectivity (KTTAA/KAATT=6). CD and DNase I footprinting studies confirmed the preference of this compound for TTAA. In summary, (i) a favorable stacking surface provided by the pi system, (ii) H-bond donors to interact with TA base pairs at the floor of the groove provided by a benzimidazole (or indole) -NH and amidines, and (iii) appropriate curvature of the dimer complex to match the curvature of the minor groove play important roles in differentiating the TTAA and AATT minor grooves.
KW - Biosensor-SPR
KW - Cooperative dimer
KW - DNA
KW - Sequence recognition
KW - TTAA
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U2 - 10.1016/j.jmb.2010.08.018
DO - 10.1016/j.jmb.2010.08.018
M3 - Article
C2 - 20713062
AN - SCOPUS:77957236488
SN - 0022-2836
VL - 402
SP - 847
EP - 864
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 5
ER -