Regioselective effect of zwitterionic DNA substitutions on DNA alkylation: Evidence for a strong side chain orientational preference

被引:27
作者
Dande, P
Liang, GN
Chen, FX
Roberts, C
Nelson, MG
Hashimoto, H
Switzer, C
Gold, B
机构
[1] UNIV NEBRASKA,MED CTR,EPPLEY INST RES CANC & ALLIED DIS,OMAHA,NE 68198
[2] UNIV NEBRASKA,MED CTR,DEPT PHARMACEUT SCI,OMAHA,NE 68198
[3] UNIV CALIF RIVERSIDE,DEPT CHEM,RIVERSIDE,CA 92521
关键词
D O I
10.1021/bi962602u
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The incorporation of zwitterionic residues (5-substituted omega-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 omega-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.
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页码:6024 / 6032
页数:9
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