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Structure and Base Pairing Properties of a Replicable Nonpolar Isostere for Deoxyadenosine.

ABSTRACT: We report the synthesis, structure, and pairing properties in DNA of an isostere for deoxyadenosine which lacks all hydrogen-bonding functionality on the Watson-Crick pairing edge. A deoxyribo-nucleoside derivative of 4-methylbenzimidazole (1), which was recently shown to be inserted into DNA by Klenow DNA polymerase (Morales, J. C.; Kool, E. T. Nature Struct. Biol.1998, 5, 950), is prepared from 1-chloro-2-deoxy-3,5-bis-O-p-toluoyl-?-D-erythro-pentofuranose. The X-ray crystal structure of the nucleoside confirms that the compound is a close steric match for deoxyadenosine (2), although the methylbenzimidazole base is in the syn glycosidic orientation in the crystal. In D(2)O solution, 1H NMR studies show that 1 and 2 have similar (60% vs 70% S) sugar conformations and anti glycosidic orientations. Compound 1 is incorporated into a 12mer oligodeoxynucleotide and its base pairing properties in duplexes assessed by thermal denaturation. The results show that 1 has low affinity for the four natural bases but displays a stronger preference for being situated opposite a nonpolar difluorotoluene nucleoside analogue of thymine (3). The structural similarities of 1 and 2, combined with recent polymerase studies, add support to the hypothesis that steric complementarity plays an important role in base pair replication by polymerase enzymes and that Watson-Crick hydrogen bonds are not absolute requirements. Compound 1 should have significant utility as a probe of the importance of electrostatic effects in protein-DNA and protein-nucleotide binding as well as in DNA replication.

SUBMITTER: Guckian KM

PROVIDER: S-EPMC2939748 | biostudies-literature | 1998

REPOSITORIES: biostudies-literature

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Structure and Base Pairing Properties of a Replicable Nonpolar Isostere for Deoxyadenosine.

Guckian Kevin M KM Morales Juan C JC Kool Eric T ET

The Journal of organic chemistry 19980101 26

We report the synthesis, structure, and pairing properties in DNA of an isostere for deoxyadenosine which lacks all hydrogen-bonding functionality on the Watson-Crick pairing edge. A deoxyribo-nucleoside derivative of 4-methylbenzimidazole (1), which was recently shown to be inserted into DNA by Klenow DNA polymerase (Morales, J. C.; Kool, E. T. Nature Struct. Biol.1998, 5, 950), is prepared from 1-chloro-2-deoxy-3,5-bis-O-p-toluoyl-α-D-erythro-pentofuranose. The X-ray crystal structure of the n ...[more]

PMID: 20852720

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Project description:The chemical synthesis of ribonucleic acids (RNA) with novel chemical modifications is largely driven by the motivation to identify eligible functional probes for the various applications in life sciences. To this end, we have a strong focus on the development of novel fluorinated RNA derivatives that are powerful in NMR spectroscopic analysis of RNA folding and RNA ligand interactions. Here, we report on the synthesis of 2'-SCF3 pyrimidine nucleoside containing oligoribonucleotides and the comprehensive investigation of their structure and base pairing properties. While this modification has a modest impact on thermodynamic stability when it resides in single-stranded regions, it was found to be destabilizing to a surprisingly high extent when located in double helical regions. Our NMR spectroscopic investigations on short single-stranded RNA revealed a strong preference for C2'-endo conformation of the 2'-SCF3 ribose unit. Together with a recent computational study (L. Li, J. W. Szostak, J. Am. Chem. Soc. 2014, 136, 2858-2865) that estimated the extent of destabilization caused by a single C2'-endo nucleotide within a native RNA duplex to amount to 6 kcal mol(-1) because of disruption of the planar base pair structure, these findings support the notion that the intrinsic preference for C2'-endo conformation of 2'-SCF3 nucleosides is most likely responsible for the pronounced destabilization of double helices. Importantly, we were able to crystallize 2'-SCF3 modified RNAs and solved their X-ray structures at atomic resolution. Interestingly, the 2'-SCF3 containing nucleosides that were engaged in distinct mismatch arrangements, but also in a standard Watson-Crick base pair, adopted the same C3'-endo ribose conformations as observed in the structure of the unmodified RNA. Likely, strong crystal packing interactions account for this observation. In all structures, the fluorine atoms made surprisingly close contacts to the oxygen atoms of the corresponding pyrimidine nucleobase (O2), and the 2'-SCF3 moieties participated in defined water-bridged hydrogen-bonding networks in the minor groove. All these features allow a rationalization of the structural determinants of the 2'-SCF3 nucleoside modification and correlate them to base pairing properties.

Dataset Information

Structure and Base Pairing Properties of a Replicable Nonpolar Isostere for Deoxyadenosine.

Publications

Structure and Base Pairing Properties of a Replicable Nonpolar Isostere for Deoxyadenosine.

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