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

The 2′-deoxynucleoside containing the synthetic base 1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl) -1H-perimidin-2(3H)-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 O ⁶-Bn-dG and dG in DNA. The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G⁴ has been replaced by O⁶-Bn-dG and cytosine C⁹ has been replaced with dPer to form the modified O⁶-Bn-dG:dPer (DDD-XY) duplex [5′-d(C ¹G²C³X⁴A⁵A ⁶T⁷T⁸Y⁹G¹⁰C ¹¹G¹²)-3′]₂ (X =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 C⁹ is replaced with dPer to form the dG:dPer (DDD-GY) [5′-d(C¹G ²C³G⁴A⁵A⁶T ⁷T⁸Y⁹G¹⁰C¹¹G 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.