Abstract
The (4′→6′)-linked DNA homolog 2′,3′-dideoxy-β-D-glucopyranosyl nucleic acid (dideoxy-glucose nucleic acid or homo-DNA) exhibits stable self-pairing of the Watson–Crick and reverse-Hoogsteen types, but does not cross-pair with DNA. Molecular modeling and NMR solution studies of homo-DNA duplexes pointed to a conformation that was nearly devoid of a twist and a stacking distance in excess of 4.5 Å. By contrast, the crystal structure of the homo-DNA octamer dd(CGAATTCG) revealed a right-handed duplex with average values for helical twist and rise of ca. 15° and 3.8 Å, respectively. Other key features of the structure were strongly inclined base-pair and backbone axes in the duplex with concomitant base-pair slide and cross-strand stacking, and the formation of a dimer across a crystallographic dyad with inter-duplex base swapping. To investigate the conformational flexibility of the homo-DNA duplex and a potential influence of lattice interactions on its geometry, we used molecular dynamics (MD) simulations of the crystallographically observed dimer of duplexes and an isolated duplex in the solution state. The dimer of duplexes showed limited conformational flexibility, and key parameters such as helical rise, twist, and base-pair slide exhibited only minor fluctuations. The single duplex was clearly more flexible by comparison and underwent partial unwinding, albeit without significant lengthening. Thus, base stacking was preserved in the isolated duplex and two adenosines extruded from the stack in the dimer of duplexes were reinserted into the duplex and pair with Ts in a Hoogsteen mode. Our results confirmed that efficient stacking in homo-DNA seen in the crystal structure of a dimer of duplexes was maintained in the separate duplex. Therefore, lattice interactions did not account for the different geometries of the homo-DNA duplex in the crystal and earlier models that resembled inclined ladders with large base-pair separations that precluded efficient stacking.
Highlights
Numerous carbohydrate moieties in place of the natural 20 -deoxyribose and ribose sugars within the framework of a phosphodiester backbone have been analyzed in terms of their potential to self-pair and/or cross-pair with DNA and RNA as part of systematic explorations of a chemical etiology of nucleic acid structure [1,2,3,4,5,6,7]
Homo-DNA oligonucleotides were found thewith beginning of this research were motivated question
Given the higher rigidity of the hexose sugar duplexes with Watson–Crick base pairing that were of higher stability than those by the corresponding compared with 2′-deoxyribose, homo-DNA’s increased pairing stability is mainly due to the entropic
Summary
Numerous carbohydrate moieties in place of the natural 20 -deoxyribose and ribose sugars within the framework of a phosphodiester backbone have been analyzed in terms of their potential to self-pair and/or cross-pair with DNA and RNA as part of systematic explorations of a chemical etiology of nucleic acid structure [1,2,3,4,5,6,7]. 2 duplex qualitative conformational analysis that assumed idealstrongly synclinal or antiperiplanar backbone (average +44◦ in the crystallographic model) and sliding between adjacent base pairs (average +4.4 Å angles [14], molecular mechanics [14], and molecular dynamics simulations [15], or was determined in the crystallographic model) [17] The latter parameter indicates that stacking in homo-DNA occurs by solution. Adjacent bases from the same strand form virtually the [dd(CGAATTCG)]2 duplex in the crystal, they displayed strongly inclined base-pair and backbone axes (average +44° in the crystallographic model) and sliding between adjacent base pairs (average +4.4 Å in the crystallographic model) [17] The latter parameter indicates that stacking in homo-DNA occurs mainly between bases from opposite strands. To investigate a potential effect of the crystal lattice on the conformation of the homo-DNA octamer duplex [dd(CGAATTCG)]2 , we probed formation of the complex in solution using
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