Stereochemistry Modulates the Stability of Reduced Interstrand Cross-Links Arising from R- and S-α-CH3-γ-OH-1,N2-Propano-2‘-deoxyguanosine in the 5‘-CpG-3‘ DNA Sequence

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Abstract
The solution structures of 5‘-Cp-N2-dG-3‘-R-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ and 5‘-Cp-N2-dG-3‘-S-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ interstrand DNA cross-links in the 5‘-CpG-3‘ sequence were determined by NMR spectroscopy. These were utilized as chemically stable surrogates for the corresponding carbinolamine interstrand cross-links arising from the crotonaldehyde- and acetaldehyde-derived R- and S-α-CH3-γ-OH-1,N2-propanodeoxyguanosine adducts. The results provide an explanation for the observation that interstrand cross-link formation in the 5‘-CpG-3‘ sequence by the R- and S-α-CH3-γ-OH-1,N2-propanodeoxyguanosine adducts is dependent upon stereochemistry, favoring the R-α-CH3-γ-OH-1,N2-propanodeoxyguanosine adduct [Kozekov, I. D., Nechev, L. V., Moseley, M. S., Harris, C. M., Rizzo, C. J., Stone, M. P., and Harris, T. M. (2003) J. Am. Chem. Soc. 125, 50−61]. Molecular dynamics calculations, restrained by NOE-based distances and empirical restraints, revealed that both the 5‘-Cp-N2-dG-3‘-R-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ and 5‘-Cp-N2-dG-3‘-S-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ cross-links were located in the minor groove and retained Watson−Crick hydrogen bonds at the tandem cross-linked C·G base pairs. However, for the 5‘-Cp-N2-dG-3‘-R-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ cross-link, the (α)-CH3 group was positioned in the center of the minor groove, whereas for the 5‘-Cp-N2-dG-3‘-S-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ cross-link, the (α)-CH3 group was positioned in the 3‘ direction, showing steric interference with the DNA helix. The 5‘-Cp-N2-dG-3‘-S-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ cross-link exhibited a lower thermal stability as evidenced by NMR spectroscopy as a function of temperature. The two cross-links also exhibited apparent differences in the conformation of the interstrand three-carbon cross-link, which may also contribute to the lower apparent thermodynamic stability of the 5‘-Cp-N2-dG-3‘-S-(α)-CH3-propyl-5‘-Cp-N2-dG-3‘ cross-link.

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