Inter-strand C-H...O hydrogen bonds stabilizing four-stranded intercalated molecules: stereoelectronic effects of O4' in cytosine-rich DNA.

Abstract

DNA fragments with stretches of cytosine residues can fold into four-stranded structures in which two parallel duplexes, held together by hemiprotonated cytosine-cytosine+ (C C+) base pairs, intercalate into each other with opposite polarity. The structural details of this intercalated DNA quadruplex have been assessed by solution NMR and single crystal x-ray diffraction studies of cytosinerich sequences, including those present in metazoan telomeres. A conserved feature of these structures is the absence of stabilizing stacking interactions between the aromatic ring systems of adjacent C-C+ base pairs from intercalated duplexes. Effective stacking involves only the exocyclic keto groups and amino groups of the cytidine bases. The apparent absence of stability provided by stacking interactions between the bases in this intercalated DNA has prompted us to examine the available structures in detail, in particular with regard to unusual features that could compensate for the lack of base stacking. In addition to base-on-deoxyribose stacking and intra-cytidine C-H..0 hydrogen bonds, this analysis reveals the presence of a hitherto unobserved, systematic intermolecular C-H*--O hydrogen bonding network between the deoxyribose sugar moieties of antiparallel backbones in the four-stranded molecule.The DNA intercalation motif, a four-stranded arrangement of two parallel intercalating duplexes using C-C+ base pairs, is adopted by a variety of cytosine-rich DNA fragments. Detailed NMR or x-ray diffraction studies were conducted thus far for (5), and d(TAACCC) (6). In the four crystal structures (2,3,5,6) the intercalated cytosine segments show a globally similar arrangement, with the remaining nucleotides folded into a variety of motifs, including A-A-T base triplets (5) and trinucleotide loops (6). Important geometrical features displayed by the two parallel-stranded duplexes forming the intercalation motif are a slow right-handed helical twist (12-20°), a rise of approximately 6.2 A between covalently linked residues, and planar base pairing between cytosines around a 2-fold rotation axis requiring hemiprotonation at the N3 position. The two duplexes are intercalated with opposite polarity and form a quasi two-dimensional array. The structure has two broad and two narrow grooves with the antiparallel backbone pairs from intercalated duplexes in van der Waals contact in the narrow grooves. Thus, the intercalation motif is dramatically different in its architecture compared with A-, B-, or Z-form duplex DNA and also the guanine quadruplex (7, 8).It is characterized by two features, both ofwhich one is inclined to attribute as destabilizing influences. First, there is the almost complete absence of overlap between adjacent aromatic cytosine ring systems from intercalated duplexes (Fig. 1A). Second, unusually close intermolecular contacts between sugarphosphate backbones in the narrow grooves are observed, with inter-strand phosphorus-phosphorus distances as close as 5.9 A (5), presumably resulting in unfavorable ele...

Plasticity in the Primary Binding Site of Galactose/N-Acetylgalactosamine-specific Lectins

“…Recently, CϪH⅐⅐⅐O interactions in collagen triple helix (23), DNAϪprotein complex (24), thrombin-inhibitor complex (25), trypanothione reductase-trypanothione disulfide complex (26), active sites of serine hydrolases (27), and helices involving proline residues (28) have also been identified. Cytosine-rich intercalated DNA quadruplexes not only contain intra-cytidine CϪH⅐⅐⅐O hydrogen bonds but also display a systematic intermolecular CϪH⅐⅐⅐O hydrogen bonding network between the deoxyribose sugar moieties of antiparallel backbones in the four-stranded molecule (29). More recently, CϪH⅐⅐⅐O hydrogen bonds have been found in the minor grooves of A-tracts in DNA double helices (30), and, as a caveat, in cubanecar- …”

Hammerhead redux: Does the new structure fit the old biochemical data?

“…While the furanose O4 has not been modified, this type of hydrogen bond has been seen in other nucleic acid structures (Berger et al 1996), including, interestingly, the ribose at the cleavage site of the hairpin ribozyme (Alam et al 2005). Finally, for the single hydrogen bond between the amino group of G12 and the N7 of A9, removing the amino group by the G12I mutation reduces k rel , but no reliable k rel is available for the 7-deaza A9 hammerhead.…”

Strength of the CαH··O Hydrogen Bond of Amino Acid Residues

“…In fact, after some early proposals of CH⅐⅐O contacts (13)(14)(15), they were positively identified in components like sugars (16). They are now known to be prevalent in larger systems such as carbohydrates (17) and nucleic acids (18 -20), where these interactions can be prime determinants for base pairing specificity (21) or general folding motifs (22). The CH⅐⅐O bond also plays an important role in the interactions of nucleic acids with proteins (23,24) and drug binding (25)(26)(27).…”