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Review Article Use of Nucleic Acid Analogs for the Study of Nucleic Acid Interactions

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Review Article Use of Nucleic Acid Analogs for the Study of Nucleic Acid Interactions SAGE-Hindawi Access to Research Journal of Nucleic Acids Volume 2011, Article ID 967098, 11 pages doi:10.4061/2011/967098 Review Article Use of Nucleic Acid Analogs for the Study of Nucleic Acid Interactions Shu-ichi Nakano,1, 2 Masayuki Fujii,3, 4 and Naoki Sugimoto1, 2 1 Faculty of Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan 2 Frontier Institute for Biomolecular Engineering Research, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan 3 Department of Environmental and Biological Chemistry, Kinki University, 11-6 Kayanomori, Iizuka, Fukuoka 820-8555, Japan 4 Molecular Engineering Institute, Kinki University, 11-6 Kayanomori, Iizuka, Fukuoka 820-8555, Japan Correspondence should be addressed to Shu-ichi Nakano, [email protected] and Naoki Sugimoto, [email protected] Received 14 April 2011; Accepted 2 May 2011 Academic Editor: Daisuke Miyoshi Copyright © 2011 Shu-ichi Nakano et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Unnatural nucleosides have been explored to expand the properties and the applications of oligonucleotides. This paper briefly summarizes nucleic acid analogs in which the base is modified or replaced by an unnatural stacking group for the study of nucleic acid interactions. We also describe the nucleoside analogs of a base pair-mimic structure that we have examined. Although the base pair-mimic nucleosides possess a simplified stacking moiety of a phenyl or naphthyl group, they can be used as a structural analog of Watson-Crick base pairs. Remarkably, they can adopt two different conformations responding to their interaction energies, and one of them is the stacking conformation of the nonpolar aromatic group causing the site-selective flipping of the opposite base in a DNA double helix. The base pair-mimic nucleosides can be used to study the mechanism responsible for the base stacking and the flipping of bases out of a nucleic acid duplex. 1. Introduction The most common structure formed by base pairing is the right-handed double helix. The geometry of Watson- Nucleic acids have many remarkable properties that other Crick base pairs mediated by hydrogen bonding is similar molecules do not possess. The most notable property is the regardless of the nucleotide sequence, and this allows a dou- ability of sequence-specific hybridization through Watson- ble helical conformation virtually identical without disrupt- Crick base pairing. Even a short oligonucleotide sequence, ing coplanar stacking between adjacent base pairs. Interbase readily synthesized chemically and available on the market at hydrogen bonding is responsible for the association of com- a relatively low cost, can self-assemble into a defined struc- plementary bases, which is essential for the storage and re- ture and hybridize specifically to a target sequence in accor- trieval of genetic information. Hydrogen donors and accep- dance with the base pair-rule of A/T and G/C. Importantly, tors on the purine and pyrimidine bases direct the base pair the controls of the self-assembly and the hybridization are partner by forming two hydrogen bonds in the A/T pair and not difficult when one considers the interaction energy of three in the C/G pair (Figure 1(a)). According to the number nucleic acid reactions [1]. Additionally, it is possible to con- of hydrogen bonds, the C/G pair appears more stable than jugate with other molecules, such as fluorescent dyes, amino the A/T pair. However, because base stacking is formed si- acids, and nanoparticles. Thus, the methodologies that uti- multaneously with the hydrogen bonding, both interactions lize DNA and RNA oligonucleotides as a tool for technology contribute to the integrity and the thermodynamic stability such as nanomaterial and medicinal and therapeutic usages of base-paired structures. In contrast to hydrogen bonding, have become of broader interest over the past decades. the base stacking does not demand a particular interaction 2 Journal of Nucleic Acids CH3 O H H N N N H C1 N N O Hydrogen bonding T N N C1 A Stacking N N O C1 H H N N N H G N N H H N O Compensatory interaction C1 C (a) (b) Figure 1: (a) Watson-Crick A/T and C/G base pairs. C1 represents the 1 carbon atom of deoxyribose in DNA. (b) Interbase hydrogen bonding and stacking interactions formed in a DNA duplex. A compensatory relationship is suggested between the interaction energies of the hydrogen bonding and the base stacking. partner, while the interaction energy between purine bases manipulating known loop interactions [11–13]. Interest- is usually greater than that between pyrimidine bases due to ingly, the quantitative data suggest that the free energies for the larger overlapping area of purine bases. The strength of forming a single hydrogen bond and the stacking interaction the stacking interaction has particular relevance to the con- are comparable to each other, providing from –0.2 to −1 ΔG◦ formation of unpaired nucleotides, for example, single- –1.8 kcal mol in 37 under a competitive correlation stranded overhangs and the helical junction containing a (Figure 1(b)), where the base pairing with a lower hydrogen nick site, whether stacked or bent [2–5].Thedegreeofstack- bond energy provides a greater stacking energy [11]. The ing is also important for the design of fluorescent dye mol- phenomenon can be accounted for by assuming the interac- ecules attached to an oligonucleotide [6]. It is an important tion mechanism in which the geometry optimized for inter- feature in nucleic acids that the base pair is formed in concert base hydrogen bonding is not suitable for base stacking and with the binding of cations and water molecules. Because the vice versa. On the other hand, investigations of the coaxial base pairing brings the sugar-phosphate backbones close to stacking of nicked and gapped sites suggest that base stacking each other which increases the electrostatic repulsion be- is the major stabilizing factor in a double helical structure of tween the phosphate groups, counterions must bind to nu- DNA [3, 5]. Studies on the stacking interaction are important cleic acids through Coulomb interaction [7]. Formation of for understanding not only the fundamental aspects of nu- the base pairs also accompanies rearrangements of the hy- cleic acid interactions but also the biological processes in- dration layer surrounding nucleic acid chains, especially volving base pair formation and strand opening, such as around the bases and within the helical grooves [8, 9]. DNA replication and refolding of nucleic acid structures. The nearest-neighbor model is widely used to account Many unnatural nucleosides have been explored accord- for the thermodynamic behavior of Watson-Crick duplexes. ing to various demands of researchers. They have been mod- The model assumes that the base pair formation is mostly ified or replaced the nucleotide base (C5-modified uridine affected by adjacent (nearest-neighbor) base pairs by taking nucleosides, N3-modified cytidine nucleosides, nonpolar into account the contributions from base stacking as well as nucleosides replaced with an aromatic hydrocarbon group, interbase hydrogen bonding. Nearest-neighbor parameters etc.) or the sugar-phosphate backbone (2-O-modified RNA, for base pairing have been extensively investigated, and the phosphorothioate DNA, morpholino oligonucleotide, pep- ◦ ΔG◦ Gibbs free energy at 37 C( 37) that ranges from –0.2 to tide nucleic acid, locked nucleic acid, etc.), as introduced in –3.4 kcal mol−1 (1 kcal = 4.18 kJ) for each nearest-neighbor preceding articles (e.g., [14–16]). In this, we briefly introduce base pair is useful to predict the hybridization energy and the nucleic acid analogs possessing an unnatural stacking folding structures of DNA and RNA [2, 10]. Although the group. We also describe the nucleoside derivatives of a base energy data include contributions from the hydrogen bond- pair-mimic structure that we have examined to understand ing and the base stacking, the free-energy increments from the biochemical properties of nucleic acid interactions, for each interaction have been estimated from the studies using example, the mechanisms responsible for the nucleotide base unnatural nucleotides and dangling end residues and by stacking and the flipping of bases out of a nucleic acid duplex. Journal of Nucleic Acids 3 N NH HN O HN N N HO HO HO HO O O N O O O OH OH OH OH (a) N H H H N N N C1 N H N HN N N HN N N N N C1 H C1 O N N N N N N O N H N N N N N N C1 C1 C1 H (b) Figure 2: (a) Structures of unnatural nucleosides as a base analog with an aromatic hydrocarbon group in place of the purine and pyrimidine bases. (b) Structures of the base pair analogs that provide the interstrand crosslinking sites. The covalent bonds linking the nucleic acid bases are highlighted in blue. 2. Unnatural Nucleosides That Mimic DNA. For example, planar polycyclic surrogates possessing Nucleotide Bases fused 1–3 aromatic rings or more intercalate into a DNA duplex and perturbs the helix conformation [20–23]. The There are many reports of unnatural nucleosides developed covalently appended quinoline residue at the terminal of an for various purposes. Some are aimed at enhancing the affin- oligonucleotide also largely disrupts the DNA duplex struc- ity and selectivity in targeting to DNA and RNA sequences ture [24]. The large aromatic groups of the pyrene-modified by increasing the number of hydrogen bonding sites or by and porphyrin-modified nucleotides inserted into a DNA addition of extra aromatic rings to the pyrimidine base [14].
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