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Flexible 5-guanidino-4-nitroimidazole DNA lesions: structures and thermodynamics.

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.

SUBMITTER: Jia L

PROVIDER: S-EPMC2527740 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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Flexible 5-guanidino-4-nitroimidazole DNA lesions: structures and thermodynamics.

Jia Lei L Shafirovich Vladimir V Shapiro Robert R Geacintov Nicholas E NE Broyde Suse S

Biochemistry 20060501 21

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 ...[more]

PMID: 16716075

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Project description:MOTIVATION: Thermodynamics-based dynamic programming RNA secondary structure algorithms have been of immense importance in molecular biology, where applications range from the detection of novel selenoproteins using expressed sequence tag (EST) data, to the determination of microRNA genes and their targets. Dynamic programming algorithms have been developed to compute the minimum free energy secondary structure and partition function of a given RNA sequence, the minimum free-energy and partition function for the hybridization of two RNA molecules, etc. However, the applicability of dynamic programming methods depends on disallowing certain types of interactions (pseudoknots, zig-zags, etc.), as their inclusion renders structure prediction an nondeterministic polynomial time (NP)-complete problem. Nevertheless, such interactions have been observed in X-ray structures. RESULTS: A non-Boltzmannian Monte Carlo algorithm was designed by Wang and Landau to estimate the density of states for complex systems, such as the Ising model, that exhibit a phase transition. In this article, we apply the Wang-Landau (WL) method to compute the density of states for secondary structures of a given RNA sequence, and for hybridizations of two RNA sequences. Our method is shown to be much faster than existent software, such as RNAsubopt. From density of states, we compute the partition function over all secondary structures and over all pseudoknot-free hybridizations. The advantage of the WL method is that by adding a function to evaluate the free energy of arbitrary pseudoknotted structures and of arbitrary hybridizations, we can estimate thermodynamic parameters for situations known to be NP-complete. This extension to pseudoknots will be made in the sequel to this article; in contrast, the current article describes the WL algorithm applied to pseudoknot-free secondary structures and hybridizations. AVAILABILITY: The WL RNA hybridization web server is under construction at http://bioinformatics.bc.edu/clotelab/.

Dataset Information

Flexible 5-guanidino-4-nitroimidazole DNA lesions: structures and thermodynamics.

Publications

Flexible 5-guanidino-4-nitroimidazole DNA lesions: structures and thermodynamics.

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