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

Biochemistry
P DandeB Gold

Abstract

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 obs...Continue Reading

References

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Citations

Sep 14, 2002·Biopolymers·Barry Gold
Apr 20, 2004·Cellular Signalling·Nicole K Noren, Elena B Pasquale
Nov 23, 2006·Chemical Research in Toxicology·Barry GoldLoren D Williams
Feb 17, 2006·Nucleic Acids Research·Sarah L WilliamsLawrence J Parkhurst
Sep 15, 2007·Nucleic Acids Research·Manjori GangulyBarry Gold
Jun 11, 1999·Current Opinion in Structural Biology·L McFail-IsomL D Williams
Oct 9, 2001·Chemistry & Biology·P R HardwidgeL J Maher
Dec 21, 2004·Chemical Research in Toxicology·Soobong ParkNatalia Tretyakova
Apr 22, 2003·Chemical Research in Toxicology·Rebecca ZiegelNatalia Tretyakova
May 18, 2005·Biochemistry·Tinoush MoulaeiLoren Dean Williams

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