Flexible 5-guanidino-4-nitroimidazole DNA lesions: Structures and thermodynamics

Lei Jia, Vladimir Shafirovich, Robert Shapiro, Nicholas Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

5-Guanidino-4-nitroimidazole (NI), derived from guanine oxidation by reactive oxygen and nitrogen species, contains an unusual flexible ring-opened structure, with nitro and guanidino groups which possess multiple hydrogen bonding capabilities. In vitro primer extension experiments with bacterial and mammalian polymerases show that NI incorporates C as well as A and G opposite the lesion, depending on the polymerase. To elucidate structural and thermodynamic properties of the mutagenic NI lesion, we have investigated the structure of the modified base itself and the NI-containing nucleoside with high-level quantum mechanical calculations and have employed molecular modeling and molecular dynamics simulations in solution for the lesion in B-DNA duplexes, with four partner bases opposite the NI. Our results show that NI adopts a planar structure at the damaged base level. However, in the nucleoside and in DNA duplexes, steric hindrance between the guanidino group and its linked sugar causes NI to be nonplanar. The NI lesion can adopt both syn and anti conformations on the DNA duplex level, with the guanidino group positioned in the DNA major and minor grooves, respectively; the specific preference depends on the partner base. On the basis of hydrogen bonding and stacking interactions, groove dimensions, and bending, we find that the least distorted NI-modified duplex contains partner C, consistent with observed incorporation of C opposite NI. However, hydrogen bonding interactions between NI and partner G or A are also found, which would be compatible with the observed mismatches.

Original languageEnglish (US)
Pages (from-to)6644-6655
Number of pages12
JournalBiochemistry
Volume45
Issue number21
DOIs
StatePublished - May 30 2006

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Hydrogen Bonding
Thermodynamics
Hydrogen bonds
Nucleosides
DNA
B-Form DNA
Nucleic Acid Conformation
Reactive Nitrogen Species
Molecular modeling
Guanine
Molecular Dynamics Simulation
Sugars
Conformations
Molecular dynamics
Structural properties
Reactive Oxygen Species
Thermodynamic properties
Oxidation
Computer simulation
5-guanidino-4-nitroimidazole

ASJC Scopus subject areas

  • Biochemistry

Cite this

Flexible 5-guanidino-4-nitroimidazole DNA lesions : Structures and thermodynamics. / Jia, Lei; Shafirovich, Vladimir; Shapiro, Robert; Geacintov, Nicholas; Broyde, Suse.

In: Biochemistry, Vol. 45, No. 21, 30.05.2006, p. 6644-6655.

Research output: Contribution to journalArticle

Jia, Lei ; Shafirovich, Vladimir ; Shapiro, Robert ; Geacintov, Nicholas ; Broyde, Suse. / Flexible 5-guanidino-4-nitroimidazole DNA lesions : Structures and thermodynamics. In: Biochemistry. 2006 ; Vol. 45, No. 21. pp. 6644-6655.
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abstract = "5-Guanidino-4-nitroimidazole (NI), derived from guanine oxidation by reactive oxygen and nitrogen species, contains an unusual flexible ring-opened structure, with nitro and guanidino groups which possess multiple hydrogen bonding capabilities. In vitro primer extension experiments with bacterial and mammalian polymerases show that NI incorporates C as well as A and G opposite the lesion, depending on the polymerase. To elucidate structural and thermodynamic properties of the mutagenic NI lesion, we have investigated the structure of the modified base itself and the NI-containing nucleoside with high-level quantum mechanical calculations and have employed molecular modeling and molecular dynamics simulations in solution for the lesion in B-DNA duplexes, with four partner bases opposite the NI. Our results show that NI adopts a planar structure at the damaged base level. However, in the nucleoside and in DNA duplexes, steric hindrance between the guanidino group and its linked sugar causes NI to be nonplanar. The NI lesion can adopt both syn and anti conformations on the DNA duplex level, with the guanidino group positioned in the DNA major and minor grooves, respectively; the specific preference depends on the partner base. On the basis of hydrogen bonding and stacking interactions, groove dimensions, and bending, we find that the least distorted NI-modified duplex contains partner C, consistent with observed incorporation of C opposite NI. However, hydrogen bonding interactions between NI and partner G or A are also found, which would be compatible with the observed mismatches.",
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