Recognition of O6 -benzyl-2′-deoxyguanosine by a perimidinone-derived synthetic nucleoside: a DNA interstrand stacking interaction

Abstract

The 2′-deoxynucleoside containing the synthetic base 1-[(2 R ,4 S ,5 R )-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1 H -perimidin-2(3 H )-one] (dPer) recognizes in DNA the O6 -benzyl-2′-deoxyguanosine nucleoside ( O6 -Bn-dG), formed by exposure to N -benzylmethylnitrosamine. Herein, we show how dPer distinguishes between O6 -Bn-dG and dG in DNA. The structure of the modified Dickerson–Drew dodecamer (DDD) in which guanine at position G 4 has been replaced by O6 -Bn-dG and cytosine C 9 has been replaced with dPer to form the modified O6 -Bn-dG:dPer (DDD-XY) duplex [5′-d(C 1 G 2 C 3X4 A 5 A 6 T 7 T 8Y9 G 10 C 11 G 12 )-3′] 2 ( X = O6 -Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond. This provides a binding pocket that allows the benzyl group of O6 -Bn-dG to intercalate between Per and thymine of the 3′-neighbor A:T base pair. Nuclear magnetic resonance data suggest that a similar intercalative recognition mechanism applies in this sequence in solution. However, in solution, the benzyl ring of O6 -Bn-dG undergoes rotation on the nuclear magnetic resonance time scale. In contrast, the structure of the modified DDD in which cytosine at position C 9 is replaced with dPer to form the dG:dPer (DDD-GY) [5′-d(C 1 G 2 C 3G4 A 5 A 6 T 7 T 8Y9 G 10 C 11 G 12 )-3′] 2 duplex ( Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine.