Elena Cubero

Electron density topological analysis of the C–H⋯O anti-hydrogen bond in the fluoroform–oxirane complex

Abstract The C–H⋯O interaction in the fluoroform–oxirane complex has recently been shown to exhibit features of anti-hydrogen bonding, which is characterized by a shortening of the C–H bond and a blue-shift of the C–H stretching frequency. We present here the results of a topological analysis of the electron density following the theory of atoms in molecules in order to gain insight into the nature of the anti-hydrogen bond. The study is focused on the two energetically most stable complexes, which correspond to a planar complex with a colinear C–H⋯O bond, and a non-planar structure with a bent C–H⋯O bond. The origin of the anti-H bond is discussed in terms of the electron density changes induced upon complexation.

Destabilization of quadruplex DNA by 8-aminoguanine.

Oligonucleotides can interact in a very specific manner with homopurine–homopyrimidine sequences of double-stranded DNA by forming triple helices (triplexes) that can be used to design sequence-specific DNA-binding molecules with diagnostic or therapeutic purposes. 2] Depending on the orientation of the third strand with respect to the central polypurine Watson–Crick strand, the triplexes are classified into two main categories: i) parallel and ii) antiparallel. Parallel triplexes require protonation of N3 of cytosine to form proper Hoogsteen bonding with N7 of guanine; this implies that its formation is strongly pH dependent. On the other hand, antiparallel triplexes require no protonation and exhibit largely pH-independent binding. 8-Amino-2’-deoxyguanosine (8AG) can be found in cellular DNA as a possible intermediate in the mutagenesis of nitroalkanes. Moreover, it has been stated that 8AG stabilizes parallel and antiparallel triplexes as well as parallel duplexes, causing an increase in the free energy of formation of 1– 4 kcalmol 1 per substitution. By using parallel and antiparallel clamps carrying the 8AG-containing strand linked to the Hoogsteen strand, it is possible to obtain DNA probes with very high affinity to single-stranded polypyrimidine targets. 8] Unfortunately, G-rich oligonucleotides easily form undesired intraor intermolecular G-tetrad structures. Thus, the ability of antiparallel clamps to form a triple-helical structure with its polypyrimidine target can be reduced by the formation of Gquartets. This has fueled the design of modified nucleobases that can destabilize the tetraplex; unfortunately, in most cases, these nucleobases also destabilize the triplex. Considering the large triplex-stabilizing effect of 8AG, we decided to test whether G tetrads were affected by the presence of 8AG residues. We selected the 15-base-long thrombin aptamer 5’GGTTGGTGTGGTTGG-3’ as a model for quadruplex-forming oligonucleotides (Scheme 1). It was shown that this oligonucleotide adopts a monomeric chair quadruplex structure in the presence of potassium and is characterized by a denaturation–renaturation profile that is reversible and can be observed by different techniques.

Parallel-Stranded Hairpins Containing 8-Aminopurines. Novel Efficient Probes for Triple-Helix Formation

We describe novel oligomers with a greater propensity to form triplexes than oligomers containing only natural bases. They consist of a polypyrimidine sequence linked head-to-head with a polypurine sequence carrying one or several 8-aminoadenine or 8-aminoguanines. The presence of 8-aminopurines also stabilised the parallel-stranded duplex structure.

Structural Properties of G,T-Parallel Duplexes

The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex.