Regioselective Effect of Zwitterionic DNA Substitutions on DNA Alkylation:  Evidence for a Strong Side Chain Orientational Preference

The incorporation of zwitterionic residues (5-substituted ω-aminoalkyl-2‘-deoxypyrimidines) into DNA has been reported to bend DNA as measured by aberrant gel mobility [Strauss et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 9515−9520]. Herein we report that DNA methylation by N-methyl-N-nitrosourea...

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Bibliographic Details
Published in:Biochemistry (Easton) 1997-05, Vol.36 (20), p.6024-6032
Main Authors: Dande, Prasad, Liang, Gangning, Chen, Fa-Xian, Roberts, Christopher, Nelson, Marek G, Hashimoto, Hiromasa, Switzer, Christopher, Gold, Barry
Format: Article
Language:English
Subjects:
Circular Dichroism
Computer Simulation
Deoxycytidine - analogs & derivatives
Deoxyuridine - analogs & derivatives
DNA - chemistry
DNA Methylation
Ions
Isomerism
Methylnitrosourea - chemistry
Models, Molecular
Nucleic Acid Conformation
Sulfuric Acid Esters - chemistry
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Summary:The incorporation of zwitterionic residues (5-substituted ω-aminoalkyl-2‘-deoxypyrimidines) into DNA has been reported to bend DNA as measured by aberrant gel mobility [Strauss et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 9515−9520]. Herein we report that DNA methylation by N-methyl-N-nitrosourea at N7-guanine is regioselectively inhibited by point substitutions of the zwitterionic residues 5-(6-aminohexyl)-2‘-deoxycytidine, 5-(6-aminohexyl)-2‘-deoxyuridine, or 5-(3-aminopropyl)-2‘-deoxyuridine. No inhibition is observed for DNA methylation by dimethyl sulfate. On the basis of inhibition patterns for methylation with the different zwitterionic substitutions and the different length tethers, the ω-aminoalkyl side chains prefer to adopt a conformation that points them toward the 3‘-base. Molecular modeling grid searches, coupled with energy minimizations, and simulated annealing molecular dynamics studies indicate that unfavorable steric interactions with the 5‘-base and backbone, as well as stabilizing electrostatic interactions with electronegative atoms on the 3‘-side, are responsible for the observed conformational preference. No evidence for association of the cationic side chain with the phosphate backbone is observed. The observed bending of DNA induced by the tethered ammonium ions may simply arise from their localization in the major groove.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi962602u