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Synthesis, Thermal Stability, Biophysical Properties, and Molecular Modeling of Oligonucleotides of RNA Containing 2′‑O‑2-Thiophenylmethyl Groups

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posted on 01.09.2016, 00:00 by Joseph C. Nguyen, Yannick Kokouvi Dzowo, Carly Wolfbrandt, Justin Townsend, Stanislav Kukatin, Haobin Wang, Marino J. E. Resendiz
Dodecamers of RNA [CUACGGAAUCAU] were functionalized with C2′-O-2-thiophenylmethyl groups to obtain oligonucleotides 1014 and 17. The modified nucleotides were incorporated into RNA strands via solid-phase synthesis. The biophysical properties of these ONs were used to quantify the effects of this modification on RNA:RNA and RNA:DNA duplexes. A combination of UV–vis and circular dichroism were used to determine thermal stabilities of all strands, which hybridized into A-form geometries. Destabilization of the double stranded RNA was measured as a function of number of consecutive modifications, reflected in decreased thermal denaturation values (ΔTm, ca. 2.5–11.5 °C). Van’t Hoff plots on a duplex containing one modification (10:15) displayed a ca. ΔΔG° of +4 kcal/mol with respect to its canonical analogue. Interestingly, hybridization of two modified strands (13:17, containing a total of eight modifications) resulted in increased stability and a distinct secondary structure, reflected in its CD spectrum. Molecular modeling based on DFT calculations shed light on the nature of this stability, with induced changes in the torsional angle δ (C5′-C4′-C3′-O3) and phosphate-phosphate distances that are in agreement with a compacted structure. The described synthetic methodology and structural information will be useful in the design of thermodynamically stable structures containing chemically reactive modifications.

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