Solution Structure of the Na⁺ form of the Dimeric Guanine Quadruplex [d(G₃T₄G3)]₂

Abstract

The solution structure of the DNA quadruplex formed by the association of two strands of the DNA oligonucleotide, d(G3T4G3), in NaCl solution has been determined by 1H two‐dimensional NMR techniques, full relaxation matrix calculations and restrained molecular dynamics. The refined structure incorporates the sequences 5′‐GlsG2AG3AT4AT5AT6AT7AG8sG9AG10A‐3′ and 5′‐G11sG12AG13AT14AT15A. T16AT17AG18sG19sG20A‐3′ (where S and A denote syn and anti, respectively) in a three‐quartet, diagonal‐looped structure that we [Strahan, G. D., Shafer, R. H. & Keniry, M. A. (1994) Nucleic Acids Res. 22, 5447–5455] and others [Smith, F. W., Lau, F. W. & Feigon, J. (1994) Proc. Natl Acad. Sci. USA 91, 10546–10550] have described. The loop structure is compact and incorporates many of the features found in duplex hairpin loops including base stacking, intraloop hydrogen bonding and extensive van der Waals' interactions. The first and third loop thymines stack over the outermost G‐quartet and are also associated by hydrogen bonding. The second and the fourth loop thymines fold inwards in order to enhance van der Waals' interactions. The unexpected sequential syn‐syn deoxyguanosines in the quadruplex stem appear to be a direct consequence of the way DNA oligonucleotides fold and the subsequent search for the most stable loop structure. The implications of loop sequence and length on the structure of quadruplexes are discussed.

Specific Inhibition of HER-2/neu Transcription Initiation

“…The Hoogsteenbonding of the guanine tetrads is favored by the presence of a monovalent cation, especially potassium, which fits within a central core formed by the carbonyl groups of the guanines (30,31). Intermolecular guanine quadruplexes can form from the association of two or four strands of DNA (or RNA), and such structures may form under physiological conditions by the human immunodeficiency virus RNA and by some guanine-rich aptameric oligonucleotides (32)(33)(34)(35)(36)(37)(38)(39). Intramolecular guanine quadruplexes form by the folding of a single strand, and guanine-rich sequences that are potentially capable of forming these structures can be found in telomeric DNA from humans, most eukaryotes, and several lower organisms (40)(41)(42)(43)(44)(45)(46)(47)(48)(49).…”

Electrostatics dominate quadruplex stability

“…For example, the sequence d(G 3 T 4 G 3 ) forms a two-stranded quadruplex in the presence of excess amounts of either Na þ or K þ . [33][34][35] In contrast to the unimolecular quadruplexes, addition of near stoichiometric amounts of Ba 2þ , for example, results in virtually no quadruplex formation, as illustrated in Figure 2. However, if methanol is present, then a peak near 300 nm, indicative of antiparallel quadruplex formation, appears.…”

Inhibition of Human Immunodeficiency Virus Type 1 Activity In Vitro by a New Self-Stabilized Oligonucleotide with Guanosine-Thymidine Quadruplex Motifs

“…Binding of NMM to the 12-mer (dG4T4G4) quadruplex DNA was examined and compared to that of the duplex DNA. There were essentially no absorption changes in the presence of duplex calf thymus DNA, while significant absorption changes occurred in the presence of the dG4T4G4 quadruplex DNA, which forms the dimeric hairpin guanosine quadruplex (basket type structure), dG4T4G4 (2,19,39).…”

“…More recently, a few workers have described the interactions of short, G-rich oligonucleotides, which also interfere with the gp120-CD4 interaction or HIV integrase activity, and were found to have anti-HIV-1 activity (1,5,7,14,18,22,27,38,46). Physical characterizations of these oligonucleotides have demonstrated that they form tetramers stabilized by G quartets (16,17,19,28,39). This G quartet motif leads to remarkable anti-HIV-1 activity.…”

“…These results suggest that all four types of quadruplex DNAs significantly changed the absorption spectrum of NMM, while the control oligonucleotide, dT10-s, did not. The dimeric hairpin guanosine quadruplex, dG3T4G3-s, has increased stability compared to the four-stranded guanosine quadruplex, dG10-s (2,19,39).…”