The Nonmutagenic (R)- and (S)-β-(N⁶-Adenyl)styrene Oxide Adducts Are Oriented in the Major Groove and Show Little Perturbation to DNA Structure^†

Conformations of (R)-β-(N⁶-adenyl)styrene oxide and (S)-β-(N⁶-adenyl)styrene oxide adducts at position X⁶ in d(CGGACXAGAAG)·d(CTTCTTGTCCG), incorporating codons 60, 61 (underlined), and 62 of the human N-ras protooncogene, were refined from ¹H NMR data. These were designated as the β-R(61,2) and β-S(61,2) adducts. A total of 533 distance restraints and 162 dihedral restraints were used for the molecular dynamics calculations of the β-S(61,2) adduct, while 518 distances and 163 dihedrals were used for the β-R(61,2) adduct. The increased tether length of the β-adducts results in two significant changes in adduct structure as compared to the corresponding α-styrenyl adducts [Stone, M. P., and Feng, B. (1996) Magn. Reson. Chem. 34, S105−S114]. First, it reduces the distortion introduced into the DNA duplex. For both the β-R(61,2) and β-S(61,2) adducts, the styrenyl moiety was positioned in the major groove of the duplex with little steric hindrance. Second, it mutes the influence of stereochemistry at the α-carbon such that both the β-R(61,2) and β-S(61,2) adducts exhibit similar conformations. The results were correlated with site-specific mutagenesis experiments that revealed the β-R(61,2) and β-S(61,2) adducts were not mutagenic and did not block polymerase bypass.