Glucose–Nucleobase Pseudo Base Pairs: Biomolecular Interactions within DNA

Abstract

Noncovalent forces rule the interactions between biomolecules. Inspired by a biomolecular interaction found in aminoglycoside-RNA recognition, glucose-nucleobase pairs have been examined. Deoxyoligonucleotides with a 6-deoxyglucose insertion are able to hybridize with their complementary strand, thus exhibiting a preference for purine nucleobases. Although the resulting double helices are less stable than natural ones, they present only minor local distortions. 6-Deoxyglucose stays fully integrated in the double helix and its OH groups form two hydrogen bonds with the opposing guanine. This 6-deoxyglucose-guanine pair closely resembles a purine-pyrimidine geometry. Quantum chemical calculations indicate that glucose-purine pairs are as stable as a natural T-A pair.

Glucose-nucleobase pairs within DNA: impact of hydrophobicity, alternative linking unit and DNA polymerase nucleotide insertion studies

“…We have recently reported melting temperatures ( T m ) for DNA duplexes containing monosaccharides linked through a flexible glycerol spacer. 15 When compared to a natural DNA base pair (T-A) in the same DNA context, we observed a decrease in T m of 14.7–19.4 °C for pairs of glc and 6dglc with DNA bases ( Table 1 ). Part of this loss in DNA stability can be attributed to the larger volume of the pyranose ring, but most of it seems to be due to the use of a flexible linker.…”

“…We had previously observed that a GNA duplex with a single 6dglc-nucleobase pair inside decreased its stability by 11.9 °C with respect to the GNA duplex. 15 However, the selectivity displayed by this type of pair (6dglc-purine vs. 6dglc-pyrimidine) was much higher in GNA than in DNA. Since the wide pyranose ring of the monosaccharide could be highly disrupting the helix structure, we decided to incorporate two or four contiguous and alternating 6dglc-nucleobase pairs trying to counteract this effect.…”

“…Connection of the glucose unit with the phosphodiester backbone of DNA was carried out through a flexible glycerol linker as a first and simple approach. 15 We have used standard phosphoramidite chemistry for the preparation of the corresponding carbohydrate oligonucleotide conjugates (COCs). This type of conjugation is quite convenient and straight-forward and it has been reported previously for the synthesis of COCs with different applications such as improving cellular uptake of antisense oligonucleotides 24 , 25 and siRNAs, 26 – 28 preparation of potential anti-HIV drugs, 29 investigation of lectin binding to carbohydrates and glycoarrays 30 and preparation of molecular interaction probes.…”

“…The analogue of glc containing the ( R )-glycerol linker, the glc( R )GY DMT-phosphoramidite derivative 12 , was synthesized following the same methodology reported previously starting from ( R )-(–)-1,2-isopropylideneglycerol 8 ( Scheme 2 ). 15 …”

“… 14 Recently, we have placed a 6-deoxyglucose-guanine pair inside a DNA double helix to study this type of interaction. 15 The fully resolved NMR structure ( Fig. 1c and d ) showed that two hydrogen bonds are formed between H1 G-O4 6dglc and HN2 G-O3 6dglc.…”