Out-of-shape DNA minor groove binders: induced fit interactions of heterocyclic dications with the DNA minor groove.
DB921 and DB911 are benzimidazole-biphenyl isomers with terminal charged amidines. DB911 has a central meta-substituted phenyl that gives it a shape similar to those of known minor groove binding compounds. DB921 has a central para-substituted phenyl with a linear conformation that lacks the appropriate radius of curvature to match the groove shape. It is thus expected that DB911, but not DB921, should be an effective minor groove binder, but we find that DB921 not only binds in the groove but also has an unusually high binding constant in SPR experiments (2.9 x 10(8) M(-)(1), vs 2.1 x 10(7) M(-)(1) for DB911). ITC thermodynamic analysis with an AATT sequence shows that the stronger binding of DB921 is due to a more favorable binding enthalpy relative to that of DB911. CD results support minor groove binding for both compounds but do not provide an explanation for the binding of DB921. X-ray crystallographic analysis of DB921 bound to AATT shows that an induced fit structural change in DB921 reduces the twist of the biphenyl to complement the groove, and places the functional groups in position to interact with bases at the floor of the groove. The phenylamidine of DB921 forms indirect contacts with the bases through a bound water. The DB921-water pair forms a curved binding module that matches the shape of the minor groove and provides a number of strong interactions that are not possible with DB911. This result suggests that traditional views of compound curvature required for minor groove complex formation should be reevaluated.
Miao
Yi
Y
Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
Lee
Michael P H
MP
Parkinson
Gary N
GN
Batista-Parra
Adalgisa
A
Ismail
Mohamed A
MA
Neidle
Stephen
S
Boykin
David W
DW
Wilson
W David
WD
D000578:Amidines / Q000737:chemistry*; D000977:Antiparasitic Agents / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D002151:Calorimetry; D002413:Cations, Divalent / Q000737:chemistry; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D020349:Surface Plasmon Resonance; D013696:Temperature
D000578:Amidines; D000977:Antiparasitic Agents; D001562:Benzimidazoles; D002413:Cations, Divalent; C506618:DB 911; C506617:DB 921; D004247:DNA