Metal–base pairing in DNA

The use of DNA as a molecular wire in nanoscale electronic architectures would greatly benefit from its capability of sequence-specific self-assembly. Although single electrons and positive charges have been shown to be transmitted by natural DNA over a distance of several base pairs, the high ohmic resistance of unmodified oligonucleotides imposes a serious obstacle. Exchanging some or all of the Watson–Crick base pairs in DNA by metal complexes may solve this problem and evolve DNA-like materials with superior conductivity for future nano-electronic applications. The so-called metal–base pairs are formed from suitable transition metal ions and ligand-like nucleosides which are introduced into both of the two pairing strands by automated DNA synthesis. This review illustrates the basic concepts of metal–base pairing and highlights recent developments in the field.     

Combined effects of metal complexation and size expansion in the electronic structure of DNA base pairs

Novel DNA derivatives have been recently investigated in the pursuit of modified DNA duplexes to tune the electronic structure of DNA-based assemblies for nanotechnology applications. Size-expanded DNAs (e.g., xDNA) and metalated DNAs (M-DNA) may enhance stacking interactions and induce metallic conductivity, respectively. Here we explore possible ways of tailoring the DNA electronic structure by combining the aromatic size expansion with the metal-doping. We select the salient structures from our recent study on natural DNA pairs complexed with transition metal ions and consider the equivalent model configurations for xDNA pairs. We present the results of density functional theory electronic structure calculations of the metalated expanded base-pairs with various localized basis sets and exchange-correlation functionals. Implicit solvent and coordination water molecules are also included. Our results indicate that the effect of base expansion is largest in Ag-xGC complexes, while Cu-xGC complexes are the most promising candidates for nanowires with enhanced electron transfer and also for on-purpose modification of the DNA double-helix for signal detection.     

Binding of metal ions by pyrimidine base pairs in DNA duplexes

Pyrimidine base pairs in DNA duplexes selectively capture metal ions to form metal ion-mediated base pairs, which can be evaluated by thermal denaturation, isothermal titration calorimetry, and nuclear magnetic resonance spectroscopy. In this critical review, we discuss the metal ion binding of pyrimidine bases (thymine, cytosine, 4-thiothymine, 2-thiothymine, 5-fluorouracil) in DNA duplexes. Thymine-thymine (T-T) and cytosine-cytosine (C-C) base pairs selectively capture Hg(II) and Ag(I) ions, respectively, and the metallo-base pairs, T-Hg(II)-T and C-Ag(I)-C, are formed in DNA duplexes. The metal ion binding properties of the pyrimidine-pyrimidine pairs can be changed by small chemical modifications. The binding selectivity of a metal ion to a 5-fluorouracil-5-fluorouracil pair in a DNA duplex can be switched by changing the pH of the solution. Two silver ions bind to each thiopyrimidine-thiopyrimidine pair in the duplexes, and the duplexes are largely stabilized. Oligonucleotides containing these bases are commercially available and can readily be applied in many scientific fields (86 references).     

Structural,Electronic, and Optical Properties of Metallo Base Pairs in Duplex DNA: A Theoretical Insight

Using density functional theory calculations, we investigated the structural, energetic, electronic, and optical properties of recently synthesized duplex DNA containing metal‐mediated base pairs. The studied duplex DNA consists of three imidazole (Im) units linked through metal (Im‐M‐Im, M=metal) and four flanking A:T base pairs (two on each side). We examined the role of artificial base pairing in the presence of two distinctive metal ions, diamagnetic Ag⁺ and magnetic Cu²⁺ ions, on the stability of duplex DNA. We found that metal‐mediated base pairs form stable duplex DNA by direct metal ion coordination to the Im bases. Our results suggest a higher binding stability of base pairing mediated by Cu²⁺ ions than by Ag⁺ ions, which is attributed to a larger extent of orbital hybridization. We furthermore found that DNA modified with Im‐Ag⁺‐Im shows the low‐energy optical absorption characteristic of π–π*orbital transition of WC A:T base pairs. On the other hand, we found that the low‐energy optical absorption peaks for DNA modified with Im‐Cu²⁺‐Im originate from spin–spin interactions. Additionally, this complex exhibits weak ferromagnetic coupling between Cu²⁺ ions and strong spin polarization, which could be used for memory devices. Moreover, analyzing the role of counter ions (Na⁺) and the presence of explicit water molecules on the structural stability and electronic properties of the DNA duplex modified with Im‐Ag⁺‐Im, we found that the impact of these two factors is negligible. Our results are fruitful for understanding the experimental data and suggest a potential route for constructing effective metal‐mediated base pairs in duplex DNA for optoelectronic applications.     

1,3,9-Triaza-2-oxophenoxazine: An Artificial Nucleobase Forming Highly Stable Self-Base Pairs with Three AgI Ions in a Duplex

Metal-mediated base pairs (MMBPs) formed by natural or artificial nucleobases have recently been developed. The metal ions can be aligned linearly in a duplex by MMBP formation. The development of a three- or more-metal-coordinated MMBPs has the potential to improve the conductivity and enable the design of metal ion architectures in a duplex. This study aimed to develop artificial self-bases coordinated by three linearly aligned Ag^I ions within an MMBP. Thus, artificial nucleic acids with a 1,3,9-triaza-2-oxophenoxazine (9-TAP) nucleobase were designed and synthesized. In a DNA/DNA duplex, self-base pairs of 9-TAP could form highly stable MMBPs with three Ag^I ions. Nine equivalents of Ag^I led to the formation of three consecutive 9-TAP self-base pairs with extremely high stability. The complex structures of 9-TAP MMBPs were determined by using electrospray ionization mass spectrometry and UV titration experiments. Highly stable self-9-TAP MMBPs with three Ag^I ions are expected to be applicable to new DNA nanotechnologies.     

Theoretical investigation on DNA/RNA base pairs mediated by copper, silver, and gold cations

B3LYP density functional based computations were performed in order to characterize the interactions present in some Cu(+), Ag(+), and Au(+) metal ion-mediated DNA and RNA base pairs from both structural and electronic points of view. Examined systems involve as ligands canonical Watson-Crick, Hoogsteen and Wobble base pairs. Two artificial Hoogsteen base pairs were also taken into account. Binding energy values indicate that complexes involving silver cations are less stable than those in which copper or gold are present, and propose a similar behaviour for these two latter ions. The nature of the bond linking metal ions and bases was described by the NBO analysis that suggests metal coordinative interactions to be covalent. An evaluation of the dispersion contributions for the investigated systems was performed with the B3LYP-D3 functional.     

A Novel DNA Helical Wire Containing HgII‐Mediated T:T and T:G Pairs

Numerous applications of metal‐mediated base pairs (metallo‐base‐pairs) to nucleic acid based nanodevices and genetic code expansion have been extensively studied. Many of these metallo‐base‐pairs are formed in DNA and RNA duplexes containing Watson–Crick base pairs. Recently, a crystal structure of a metal–DNA nanowire with an uninterrupted one‐dimensional silver array was reported. We now report the crystal structure of a novel DNA helical wire containing Hg^II‐mediated T:T and T:G base pairs and water‐mediated C:C base pairs. The Hg‐DNA wire does not contain any Watson–Crick base pairs. Crystals of the Hg‐DNA wire, which is the first DNA wire structure driven by Hg^II ions, were obtained by mixing the short oligonucleotide d(TTTGC) and Hg^II ions. This study demonstrates the potential of metallo‐DNA to form various structural components that can be used for functional nanodevices.     

Crystal violet as a fluorescent switch-on probe for i-motif: label-free DNA-based logic gate

The first application of crystal violet as a selective fluorescent switch-on probe for i-motif DNA has been reported. This interaction has been exploited to develop a label-free DNA-based "OR" logic gate for potassium and hydrogen ions.     

Self-assembly of DNA Nanostructures via Bioinspired Metal Ion Coordination

Despite a growing interest in DNA nanomaterials,their simple synthesis remains a challenge.A simple and general strategy for constructing DNA-based nanomaterials by metal ion coordination is reported.The me-tal-DNA nanoparticles(NPs)could be synthesized with DNA molecules of diverse sequence and various metal ions of intrinsic property,resulting in multifunctional NPs with the combined advantages of both inorganic and DNA building blocks.It is demonstrated that the hybrid metal-DNA NPs could be engineered for magnetic resonance and luminescence imaging,encapsulation of multifarious nucleic acids with controlled ratio,and co-assembly with small drug molecules.Furthermore,because these metal-DNA NPs exhibited enhanced cellular uptake compared to free synthetic DNA,they hold potential for applications in diagnostics and therapeutics.     

Development of a Metal‐Ion‐Mediated Base Pair for Electron Transfer in DNA

A new C‐nucleoside structurally based on the hydroxyquinoline ligand was synthesized that is able to form stable pairs in DNA in both the absence and the presence of metal ions. The interactions between the metal centers in adjacent Cu^II‐mediated base pairs in DNA were probed by electron paramagnetic resonance (EPR) spectroscopy. The metal–metal distance falls into the range of previously reported values. Fluorescence studies with a donor–DNA–acceptor system indicate that photoinduced charge‐transfer processes across these metal‐ion‐mediated base pairs in DNA occur more efficiently than over natural base pairs.     

Contiguous metal-mediated base pairs comprising two Ag(I) ions

The incorporation of transition‐metal ions into nucleic acids by using metal‐mediated base pairs has proved to be a promising strategy for the site‐specific functionalization of these biomolecules. We report herein the formation of Ag⁺‐mediated Hoogsteen‐type base pairs comprising 1,3‐dideaza‐2′‐deoxyadenosine and thymidine. By defunctionalizing the Watson–Crick edge of adenine, the formation of regular base pairs is prohibited. The additional substitution of the N3 nitrogen atom of adenine by a methine moiety increases the basicity of the exocyclic amino group. Hence, 1,3‐dideazaadenine and thymine are able to incorporate two Ag⁺ ions into their Hoogsteen‐type base pair (as compared with one Ag⁺ ion in base pairs with 1‐deazaadenine and thymine). We show by using a combination of experimental techniques (UV and circular dichroism (CD) spectroscopies, dynamic light scattering, and mass spectrometry) that this type of base pair is compatible with different sequence contexts and can be used contiguously in DNA double helices. The most stable duplexes were observed when using a sequence containing alternating purine and pyrimidine nucleosides. Dispersion‐corrected density functional theory calculations have been performed to provide insight into the structure, formation and stabilization of the twofold metalated base pair. They revealed that the metal ions within a base pair are separated by an Ag???Ag distance of about 2.88 Å. The Ag–Ag interaction contributes some 16 kcal mol^?1 to the overall stability of the doubly metal‐mediated base pair, with the dominant contribution to the Ag–Ag bonding resulting from a donor–acceptor interaction between silver 4d‐type and 4s orbitals. These Hoogsteen‐type base pairs enable a higher functionalization of nucleic acids with metal ions than previously reported metal‐mediated base pairs, thereby increasing the potential of DNA‐based nanotechnology.     

Dispersions based on noble metal nanoparticles-DNA conjugates

Many biomolecules have specific binding properties in the nanostructure formation; they are attractive materials for nanotechnology. One such promising construction material for growing a well-defined nanostructure is deoxyribonucleic acid, due to its π-electron hydrophobic core and predictable recognition attributed to the specificity of Watson–Crick base-pairing. Hydrogen bonding provides the specificity behind the matching of complementary pairs of single-stranded (ss) DNA to hybridize into a double strand (ds) of helical DNA. The double-helical structure of DNA is determined by a subtle balance of noncovalent interactions among the DNA building blocks. The most prominent role is played by the interactions between the DNA bases, where two binding motifs can be recognized: planar hydrogen bonding and vertical stacking. DNA-based nanotechnology has generated interest in a number of applications due to the specificity, programmability, and reproducibility of DNA interaction with noble metal nanoparticles. 5′ and 3′ thiol moieties are used to prepare composite DNAs, DNA–gold nanoparticle conjugates and nanostructures with a variety of nanoparticle-based DNA assays. Particularly, color changes induced by the association of nanometer-sized gold particles provide a basis of a simple yet highly selective method for detecting specific biological reactions between anchored ligand molecules and receptor molecules in the milieu. Colloidal noble metal nanoparticles, in particular, have found application in a variety of assay formats in which analyte binding is coupled to particle adsorption. The extreme sensitivity of the bandwidth, the peak height, and the position of the absorption (or scattering) maximum of surface plasmon resonance spectra to environmental changes have prompted the development of approaches directly monitor the DNA hybridization. The same features that make DNA an effective molecule for the storage of genetic information also render it useful as an engineering material for the construction of smart objects at the nanometer scale because of its ability to self organize into desired structures via the specific hybridization of complementary sequences. Biocompatibility between gold nanomaterials and biological scaffolding is crucial to the development of smart biomaterials. These DNA/metal colloids are interesting for their fundamental properties as well as for applications in nanomaterials science and nanobiotechnology.     

Bifacial Base‐Pairing Behaviors of 5‐Hydroxyuracil DNA Bases through Hydrogen Bonding and Metal Coordination

A novel bifacial ligand‐bearing nucleobase, 5‐hydroxyuracil ( U^OH ), which forms both a hydrogen‐bonded base pair ( U^OH –A) and a metal‐mediated base pair ( U^OH –M– U^OH ) has been developed. The U^OH –M– U^OH base pairs were quantitatively formed in the presence of lanthanide ions such as Gd^III when U^OH – U^OH pairs were consecutively incorporated into DNA duplexes. This result established metal‐assisted duplex stabilization as well as DNA‐templated assembly of lanthanide ions. Notably, a duplex possessing U^OH –A base pairs was destabilized by addition of Gd^III ions. This observation suggests that the hybridization behaviors of the U^OH ‐containing DNA strands are altered by metal complexation. Thus, the U^OH nucleobase with a bifacial base‐pairing property holds great promise as a component for metal‐responsive DNA materials.     

High affinity DNAzyme-based ligands for transition metal cations - a prototype sensor for Hg2+

Inspired by recent interest in DNAzymes as transition metal ion sensors, a survey of the effects of various transition metals on the intramolecular cleavage rate of an imidazole modified, M(2+)-independent, self-cleaving "9(25)-11" DNA is reported. In particular, 9(25)-11 activity was strongly inhibited by Hg(2+)(K(d)(APP)= 110 +/- 9 nM). It is postulated that the affinity and selectivity of 9(25)-11 for Hg(2+) stems from the fact that this synthetically modified DNAzyme contains imidazoles. This study demonstrates the utility of modified nucleotides in developing DNAzyme sensors for metals ions, especially those for which unmodified nucleic acids might not serve as inherently good ligands.     

Effective modulation of DNA duplex stability by reversible transition metal complex formation in the minor groove

Herein we describe the reversible changing of DNA duplex thermal stability by exploiting transition metal complexation phenomena. A terpyridine ligand was conjugated to the N2'-atoms of 2'-amino-2'-deoxyuridine and its locked counterpart 2'-amino-LNA, and these metal-complexing monomers were incorporated into oligodeoxyribonucleotides. Upon addition of varying amounts of transition metal ions, the thermal stability of DNA duplexes containing these terpyridine-functionalized units in different constitutions was affected to different degrees (DeltaTm values = -15.5 to +49.0 degrees C, relative to the unmodified duplex). The most pronounced effects were observed when two complexing monomers were positioned in opposite strands. Addition of 1 equiv of Ni2+ to such a system induced extraordinary duplex stabilization. Molecular modeling studies suggest, as an explanation for this phenomenon, formation of nickel-mediated interstrand linkages in the minor groove. Addition of an excess of metal ions resulted in largely decreased Tm values. Alternating addition of metal ions and EDTA demonstrated reversibility of metal ion-induced changes in hybridization strength, proving that the described approach provides an efficient method for duplex stability modulation.     

Theorization on ion-exchange equilibria: activity of species in 2-D phases

Ion-exchange reactions are naturally occurring at soil and sediment/water interphases, determining soil fertility and water quality. These ion-exchange reactions with inorganic and organic exchangers are applied to chemical analysis, recovery of useful ions from low-grade ores (potentially from sea water), water purification including the preparation of "ultrapure" water, production of foods and medicines, therapy, and other uses. It is important to theorize about or to model ion-exchange reactions for quantitative explanations of ion-exchange phenomena and for efficient operation of ion-exchange processes. This paper describes the modeling of ion-exchange equilibria for hydroxyl sites on metal oxides and carboxyl sites in resins with monovalent cations (alkali metal ions), a monovalent anion (nitrate ion), and divalent heavy metal ions. The procedure of modeling is as follows: the stoichiometry and material balance equations of the respective ion-exchange reactions were established based on findings here and by others. The equilibrium conditions were given by the Frumkin equation, where the mass-action relation is modified with lateral interactions between species at the interphase. The model equations were fitted to the measured data and model parameter values were determined by nonlinear regression analysis. The formation of bonds between ions and exchanger sites was evaluated by the equilibrium constant and the suppression of bond formation by electrostatic, geometric, and other lateral interactions was evaluated by the interaction constant. It was established that the properties of ions are determined by the valence, size, and hydration state of the ions. Monovalent ions (anions and cations) react with oxide surface hydroxyl and resin carboxyl sites as hydrated ions and form loose ion-site pairs by a weak electrostatic bond (nonspecific adsorption). However, the lateral interactions are large because of a large polarization of the ion-site pairs. When the monovalent cations are dehydrated to react with carboxyl sites in narrow resin nanopores, the bond formation is difficult because energy for dehydration is necessary. The suppressive lateral interactions here are small because of a small polarization of the dehydrated ion-site pairs that are in direct contact. Divalent heavy metal ions react with oxide hydroxyl sites by replacing their hydrated water molecules and form ion-site pairs in direct strong contact (specific adsorption). The bond formation becomes easier with increasing charge density of the ions evaluated by the charge/radius ratio, agreeing with the order of these ions to form hydroxo complexes in solution. The suppressive lateral interaction is, however, small for ions with large charge densities, because a strong contact bond reduces the polarization of ion-site pairs by neutralization. The properties of exchangers are functions of the molecular and pore environments around the functional groups. The acid-base nature of oxide surface-hydroxyl groups is determined by the electronegativity of surrounding lattice metal ions, and that of resin carboxyl groups by the electron-repelling effect of adjacent methyl groups. Pores in oxides have diameters sufficient to accommodate hydrated ions, and the suppression is large because of repulsion from ions adsorbed on opposite pore walls (across-pore interaction). Pores in resins differentiate ions that can access or not access sites on the internal surfaces of the pores. Narrow nanopores with diameters less than those of the hydrated ions require ions to dehydrate before they can enter. The ion-exchange reactivity here is small, as described above for dehydrated monovalent ions. In wide nanopores where hydrated ions can enter, bond formation is easier, but suppression is greater because of a larger polarization of hydrated ion-site pairs and also of the across-pore interaction. Macropores have diameters much larger than those of the hydrated ions and the bond formation is the same as that in wide nanopores, but the suppression is smaller because of the absence oe of the absence of the across-pore interaction. Finally, this paper attempts a formulation of activity coefficients of exchanging sites and adsorbed ion-site pairs and compares the proposed activity coefficients of interphase species with that of solution species given by the Debye-Hückel equation.     

Metal–DNA Coordination-Driven Self-Assembly: A Conceptual Methodology to Expand the Repertoire of DNA Nanobiotechnology

The past several decades have witnessed a rapid revolution of DNA nanotechnology. DNA nanostructures are mainly synthesized with two approaches, by assembly of purely DNA-based nanostructures through complementary base pairing or grafting DNA onto nanoparticles (NPs). Despite the progress made, developing simple and universal methods for the synthesis of DNA nanoarchitectures with specific morphologies and functionalities is still a challenge. This article introduces the reader to a new biomimetic methodology that leads to the controlled synthesis of DNA nanoarchitectures based on metal–DNA coordination chemistry and, furthermore, demonstrates the broad biomedical applications of these functional materials. In particular, we highlight the coordination-driven 1) surface-functionalization of NPs with DNA molecules and 2) direct self-assembly of metal–DNA nanostructures. Finally, challenges and opportunities of this approach to develop nanobiotechnology are provided.     

EFFECT OF METAL IONS ON THE LUMINESCENCE OF ACRIDINE DYES BOUND TO DNA

Abstract— The luminescence of acridine dyes intercalated in DNA was studied as a function of the concurrent binding of metal ions to DNA, in an effort to deduce specific site interactions of the dyes. Two dyes, proflavine (PF) and acridine orange (AO), and two metal ions, silver and mercuric, were used. Both ions quench the fluorescence of the dyes in aqueous solution at room temperature. The metal ions have a different effect on the fluorescence of these dyes when they are intercalated between the base pairs of DNA. The fluorescence of AO is decreased when silver is bound, while the fluorescence of PF is enhanced. Since Ag⁺ initially binds to GC sites in DNA, which quench the PF fluorescence, it ostensibly 'turns off' the quenching by DNA at these sites, and this effect is greater than the quenching effect of the silver ion itself. Hg²⁺ ion initially binds to AT sites in DNA. Since both dyes fluoresce from AT sites, Hg²⁺ is expected to quench their fluorescence. This behavior is observed at low r (metal ion/base). At higher r values, however, where Hg²⁺ is expected to begin binding to GC sites, the fluorescence of PF is enhanced. These quenching turn-off effects are tentatively interpreted in terms of a change in the structure of the dye/DNA complex which occurs when a metal ion binds at the intercalation site. At 77 K. no fluorescence enhancement is observed when metal ions bind; Ag⁺ quenches the fluorescence and enhances the phosphorescence of both dyes. Qualitatively similar results are obtained with Hg²⁺.     

A DNA Structure Containing AgI‐Mediated G:G and C:C Base Pairs

Metal‐mediated base pairs have been extensively utilized in many research fields, including genetic‐code extension, novel therapeutics development, and nanodevice design. Compared to other cations, Ag^I is more flexible in pairing with natural base pairs. Herein, we present a DNA structure containing two C‐Ag^I‐C pairs and the first reported G‐Ag^I‐G pair in a short 8mer DNA strand. This structure not only provides detailed insight into these Ag^I‐mediated base‐pairing patterns in DNA, but also represents the first nonhelical DNA structure driven by heavy‐metal ions, thus further contributing to the structural diversity of DNA. This unique complex structure is highly sequence‐dependent, thus implying functional potentials as a new DNA aptamer that can bind and recognize silver ions. These results not only advance our understanding of the interactions between Ag^I and nucleobases, but also provide a unique structural component for the rational design of new DNA nanodevices.     

DNA modified with metal complexes: Applications in the construction of higher order metal–DNA nanostructures

DNA has recently emerged as a useful building block for higher order nanostructures, such as extended two-dimensional surfaces and discrete two- and three-dimensional structures. Transition metal complexes can introduce functionality to these otherwise passive nanostructures. This review examines the synthetic strategies used to introduce metals in a site-specific manner to DNA: either by attaching preformed metal complexes to DNA, or by metal coordination to unmodified or modified DNA. The applications of metal–DNA complexes in building higher order nanostructures and the utility of attaching luminescent or electrochemical labels are discussed.