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NMR structures of (rGCUGAGGCU)2 and (rGCGGAUGCU)2: probing the structural features that shape the thermodynamic stability of GA pairs.

ABSTRACT: The NMR structures of [see text] and [see text] are reported. The internal loop, [see text], is about 2 kcal/mol more stable than [see text] at 37 degrees C. The duplexes assemble into similar global folds characterized by the formation of tandem sheared GA pairs. The different stabilities of the loops are accompanied by differences in the local structure of the closing GU pairs. In the [see text] internal loop, the GU pairs form canonical wobble configurations with two hydrogen bonds, whereas in [see text], the GU pairs form a single hydrogen bond involving the amino group, GH22, and the carbonyl group, UO4. This pairing is similar to the GU closing pair of the 690 hairpin loop found in E. coli 16S rRNA. The [see text] and [see text] structures reveal how the subtle interplay between stacking and hydrogen bonding determines sequence dependent conformation and thermodynamic stability. Thus, this work provides structural and thermodynamic benchmarks for theoreticians in the ongoing effort to understand the sequence dependence of RNA physicochemical properties.

SUBMITTER: Tolbert BS

PROVIDER: S-EPMC4032317 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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NMR structures of (rGCUGAGGCU)2 and (rGCGGAUGCU)2: probing the structural features that shape the thermodynamic stability of GA pairs.

Tolbert Blanton S BS Kennedy Scott D SD Schroeder Susan J SJ Krugh Thomas R TR Turner Douglas H DH

Biochemistry 20070120 6

The NMR structures of [see text] and [see text] are reported. The internal loop, [see text], is about 2 kcal/mol more stable than [see text] at 37 degrees C. The duplexes assemble into similar global folds characterized by the formation of tandem sheared GA pairs. The different stabilities of the loops are accompanied by differences in the local structure of the closing GU pairs. In the [see text] internal loop, the GU pairs form canonical wobble configurations with two hydrogen bonds, whereas i ...[more]

PMID: 17279616

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Project description:A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4- dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A*, are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.

Dataset Information

NMR structures of (rGCUGAGGCU)2 and (rGCGGAUGCU)2: probing the structural features that shape the thermodynamic stability of GA pairs.

Publications

NMR structures of (rGCUGAGGCU)2 and (rGCGGAUGCU)2: probing the structural features that shape the thermodynamic stability of GA pairs.

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