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.     

Optimized DNA targeting using N,N-bis(2-pyridylmethyl)-beta-alanyl 2'-amino-LNA

Incorporation of N,N-bis(2-pyridylmethyl)-beta-alanyl 2'-amino-LNA (bipyridyl-functionalized 2'-amino locked nucleic acid) monomers into DNA strands enables high-affinity targeting of complementary DNA with excellent Watson-Crick selectivity in the presence of divalent metal ions. Positioning of bipyridyl-functionalized 2'-amino-LNA monomers in two complementary DNA strands in a "3'-end zipper" constitution allows modulation of duplex stability, i.e., a strong stabilizing effect with one equivalent of divalent metal ion per bipyridyl pair, or a strong destabilizing effect with an excess of divalent metal ions.     

Evaluation of effects of bivalent cations on the formation of purine-rich triple-helix DNA by ESI-FT-MS

The GGA triplet repeats are widely dispersed throughout eukaryotic genomes. (GGA)n or (GGT)n oligonucleotides can interact with double-stranded DNA containing (GGA:CCT)n to form triple-stranded DNA. The effects of 8 divalent metal ions (3 alkaline-earth metals and 5 transition metals) on formation of these purine-rich triple-helix DNA were investigated by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-MS). In the absence of metal ions, no triplex but single-strand, duplex, and purine homodimer ions were observed in mass spectra. The triple-helix DNA complexes were observed only in the presence of certain divalent ions. The effects of different divalent cations on the formation of purine-rich triplexes were compared. Transition-metal ions, especially Co²⁺ and Ni²⁺, significantly boost the formation of triple-helix DNA, whereas alkaline-earth metal ions have no positive effects on triplex formation. In addition, Ba²⁺ is notably beneficial to the formation of homodimer instead of triplex.     

Metal binding to ligand-containing peptide nucleic acids

The substitution of nucleobases in nucleic acid duplexes with ligands that have high affinity for transition metal ions creates metal-binding sites at specific locations within the duplexes. Several studies on the incorporation of metal ions into DNA and peptide nucleic acid (PNA) duplexes have suggested that the stability constant of the metal complex formed within the duplexes is a primary determinant of the thermal stability of the duplexes. To understand this relationship, we have synthesized two PNA monomers that carry the same ligand, namely 8-hydroxyquinoline, but have this ligand attached differently to the PNA backbone. The PNA monomers have been incorporated into PNA duplexes. UV and CD spectroscopy and calorimetric studies of the 8-hydroxyquinoline-PNA duplexes showed that the effect of the stability of the metal complex on the PNA duplexes was significantly modulated by the steric relationship between the complex and the duplex. This information is useful for the construction of hybrid inorganic-nucleic acid nanostructures.     

Thermal degradation and smoke suspension of cotton cellulose modified with THPC and its lanthanide metal complexes

Complexes of cell–THPC–urea–ADP with transition metal ion Co²⁺ and lanthanide metal ions such as La³⁺, Ce⁴⁺, Nd³⁺ and Sm³⁺ have been prepared. The thermal behavior and smoke suspension of the samples are determined by TG, DTA, DTG and cone calorimetry. The activation energies for the second stage of thermal degradation have been obtained by following Broido equation. Experimental data show that for the complexes of cell–THPC–urea–ADP with the metal ions, the activation energies and thermal decomposition temperatures are higher than those of cell–THPC–urea–ADP, which shows these metal ions can increase the thermal stability of cell–THPC–urea–ADP. Moreover, these lanthanide metal ions can more increase thermal stability of samples than do the transition metal ion Co²⁺. The cone calorimetry data indicate that the lanthanide metal ions, similar to transition metal Co²⁺, greatly decrease the smoke, CO and CO₂ generation of cell–THPC–urea–ADP, which can be used as smoke suppressants.     

Metal‐Ion‐Mediated Tuning of Duplex DNA Binding by Bis(2‐(2‐pyridyl)‐1H‐benzimidazole)

Studies of double‐stranded‐DNA binding have been performed with three isomeric bis(2‐(n‐pyridyl)‐1H‐benzimidazole)s (n=2, 3, 4). Like the well‐known Hoechst 33258, which is a bisbenzimidazole compound, these three isomers bind to the minor groove of duplex DNA. DNA binding by the three isomers was investigated in the presence of the divalent metal ions Mg²⁺, Co²⁺, Ni²⁺, Cu²⁺, and Zn²⁺. Ligand–DNA interactions were probed with fluorescence and circular dichroism spectroscopy. These studies revealed that the binding of the 2‐pyridyl derivative to DNA is dramatically reduced in the presence of Co²⁺, Ni²⁺, and Cu²⁺ ions and is abolished completely at a ligand/metal‐cation ratio of 1:1. Control experiments done with the isomeric 3‐ and 4‐pyridyl derivatives showed that their binding to DNA is unaffected by the aforementioned transition‐metal ions. The ability of 2‐(2‐pyridyl)benzimidazole to chelate metal ions and the conformational changes of the ligand associated with ion chelation probably led to such unusual binding results for the ortho isomer. The addition of ethylenediaminetetraacetic acid (EDTA) reversed the effects completely.     

alpha-L-ribo-configured locked nucleic acid (alpha-L-LNA): synthesis and properties

The syntheses of monomeric nucleosides and 3'-O-phosphoramidite building blocks en route to alpha-L-ribo-configured locked nucleic acids (alpha-L-LNA), composed entirely of alpha-L-LNA monomers (alpha-L-ribo configuration) or of a mixture of alpha-L-LNA and DNA monomers (beta-D-ribo configuration), are described and the alpha-L-LNA oligomers are studied. Bicyclic 5-methylcytosin-1-yl and adenine-9-yl nucleoside derivatives have been prepared and the phosphoramidite approach has been used for the automated oligomerization leading to alpha-L-LNA oligomers. Binding studies revealed very efficient recognition of single-stranded DNA and RNA target oligonucleotide strands. Thus, stereoirregular alpha-L-LNA 11-mers containing a mixture of alpha-L-LNA monomers and DNA monomers ("mix-mer alpha-L-LNA") were shown to display DeltaT(m) values of +1 to +3 degrees C per modification toward DNA and +4 to +5 degrees C toward RNA when compared with the corresponding unmodified DNA x DNA and DNA x RNA reference duplexes. The corresponding DeltaT(m) values per modification for the stereoregular fully modified alpha-L-LNA were determined to be +4 degrees C (against DNA) and +5 degrees C (against RNA). 11-Mer alpha-L-LNAs (mix-mer alpha- L-LNA or fully modified alpha- L-LNA) were shown in vitro to be significantly stabilized toward 3'-exonucleolytic degradation. A duplex formed between RNA and either mix-mer alpha-L-LNA or fully modified alpha-L-LNA induced in vitro Escherichia coli RNase H-mediated cleavage, albeit very slow, of the RNA targets at high enzyme concentrations.     

On the stability of double stranded nucleic acids

We present the first pressure-versus-temperature phase diagram for the helix-to-coil transition of double stranded nucleic acids. The thermodynamic stability of a nucleic acid duplex is a complex function of temperature and pressure and strongly depends on the denaturation temperature, T(M), of the duplex at atmospheric pressure. Depending upon T(M), pressure, and temperature, the phase diagram shows that pressure may stabilize, destabilize, or have no effect on the conformational state of DNA. To verify the phase diagram, we have conducted high-pressure UV melting experiments on poly(dIdC)poly(dIdC), a DNA duplex, poly(rA)poly(rU), an RNA duplex, and poly(dA)poly(rU), a DNA/RNA hybrid duplex. The T(M) values of these duplexes have been modulated by altering the solution ionic strength. Significantly, at low salt, these three duplexes have helix-to-coil transition temperatures of 50 degrees C or less. In agreement with the derived phase diagram, we found that the polymeric duplexes were destabilized by pressure if the T(M) is < approximately 50 degrees C. However, these duplexes were stabilized by pressure if the T(M) is > approximately 50 degrees C. The DNA/RNA hybrid duplex, poly(dA)poly(rU), with a T(M) of 31 degrees C in 20 mM NaCl undergoes a pressure-induced helix-to-coil transition at room temperature. This is the first report of pressure-induced denaturation of a nucleic acid duplex and provides new insights into the molecular forces stabilizing these structures.     

Coordination Assembly of Tetrahedral Ti4(embonate)6 Cages with Alkaline-Earth Metal Ions

Recently,the tetrahedral Ti₄L₆ cage(L=embonate)has been applied as the starting material to realize coordination assembly with transition and rare-earth ornoble metal ions through a two-step reaction.In this work,by employing the Ti₄L₆ cages to assemble with alkaline-earth metal ions(such as Mg²⁺,Ca²⁺and Ba²⁺)under different solvothermal conditions,a series of Ti₄L₆-based structures from simple cages to 1D chain,2D layer and 3D framework have been synthesized and structurally characterized.In addition,thermal stability,phase purity,UV-vis absorption spectrum,the fluorescent and third-order nonlinear-optical properties are also investigated.     

Differential interactions of plasmid DNA, RNA and endotoxin with immobilised and free metal ions

Separation of negatively charged molecules, such as plasmid DNA (pDNA), RNA and endotoxin forms a bottleneck for the development of pDNA vaccine production process. The use of affinity interactions of transition metal ions with these molecules may provide an ideal separation methodology. In this study, the binding behaviour of pDNA, RNA and endotoxin to transition metal ions, either in immobilised or free form, was investigated. Transition metal ions: Cu2+, Ni2+, Zn2+, Co2+ and Fe3+, typically employed in the immobilised metal affinity chromatography (IMAC), showed very different binding behaviour depending on the type of metal ions and their existing state, i.e. immobilised or free. In the alkaline cell lysate, pDNA showed no binding to any of the IMAC chemistries tested whereas RNA interacted significantly with Cu2+-iminodiacetic acid (IDA) and Ni2+-IDA but showed no substantial binding to the rest of the IMAC chemistries. pDNA and RNA, however, interacted to varying degrees with free metal ions in the solution. The greatest selectivity in terms of pDNA and RNA separation was achieved with Zn2+ which enabled almost full precipitation of RNA while keeping pDNA soluble. For both immobilised and free metal ions, ionic strength of solution affected the metal ion-nucleic acid interaction significantly. Endotoxin, being more flexible, was able to interact better with the immobilised metal ions than the nucleic acids and showed binding to all the IMAC chemistries. The specific interactions of immobilised and/or free metal ions with pDNA, RNA and endotoxin showed a good potential, by selectively removing RNA and endotoxin at high efficiency, to develop a simplified pDNA purification process with improved process economics.     

Modification of 4-(2-pyridylazo)-resorcinol postcolumn reagent selectivity through competitive equilibria with chelating ligands

Aminopolycar☐ylate ligands were added to the 4-(2-pyridylazo)-resorcinol (PAR) postcolumn reagent to alter the reagent selectivity towards transition metals. Addition of ethylenediaminetetraacetic acid (EDTA) completely suppressed the reaction between PAR and the metal ions. Addition of 0.1 mM nitrilotriacetic acid (NTA) to 1 mM PAR lowered the response to specific transition metal ions, but completely suppressed the PAR response to the lanthanides. Increasing the NTA concentration to 8 mM resulted in complete suppression of the PAR response to all metal ions except Cu²⁺ and Co²⁺ for which the detection limits were 3 and 1 ng, respectively. The observed selectivity results from the slow rate of conversion of metal ions from the M(NTA)₂⁴⁻ form to M(PAR)₂.     

Formation of silver(I)-mediated DNA duplex and triplex through an alternative base pair of pyridine nucleobases

We have recently reported the first artificial nucleoside for alternative DNA base pairing through metal complexation (J. Org. Chem. 1999, 64, 5002-5003). In this context, we have accomplished a Ag(I)-mediated base pair or a base triplet in a double- or triple-stranded DNA, respectively, by introducing a pair of pyridine nucleobases in the middle of the sequence. As a result, the incorporated Ag(I) complex significantly stabilized the DNA duplex and triplex. This strategy would be expanded to the regulation of thermodynamic stability of DNA duplex or triplex by adding transition metal ions from outside, or to labeling applications in biotechnology.     

识别过渡金属离子的1,8-萘二甲酰亚胺多胺衍生物荧光传感器的研究

A series of fluorescent chemosensors 1-3 were synthesized to detect transition metal ions. At the room temperature, fluorescence intensities of these chemosensors in acetonitrile without transition metal ions were found to be very weak, due to the process of the e±cient intramolecular photoinduced electron transfer (PET). However, after addition of the transition metal ions, the chemosensor 1-3 exhibits obvious fluorescence enhancement. Moreover, the intensity of the fluorescence emission of chemosensors increases significantly in the presence of Zn2+ and Cd2+. The fluorescent chemosensors with different polyamine as receptors show diverse a±nity abilities to the transition metal ions and signal the receptor-metal ion interaction by the intensity change of fluorescence emission.     

New insights into the anti-hepatoma mechanism of Alisol G-metal ions complexes based on c-myc DNA

This study investigated the anti-hepatoma molecular mechanism of Alisol G, which is an effective component of the Chinese medicine Alisma orientalis, in the presence of metal ions Cu²⁺ and Fe³⁺ based on c-myc DNA. Here, a combination of Alisol G and metal ions (Cu²⁺, Fe³⁺) to augment anti-hepatoma efficiencies of Alisol G has been identified by methyl thiazolyl tetrazolium (MTT) assay. Network pharmacology revealed that c-myc DNA was the potential target of Alisol G with respect to its anti-hepatoma effects. By performing multi-spectroscopic analyses, we showed that the interaction of Alisol G with c-myc DNA was a process of static quenching. The binding constants and thermodynamic constants indicated that a 1:1 complex was formed between Alisol G and c-myc DNA. Moreover, metal ions strengthened the interaction between Alisol G and c-myc DNA. Molecular docking and molecular dynamics simulation further unveiled that the higher binding affinity between Alisol G-Fe³⁺ complex and c-myc DNA as compared to Alisol G-Cu²⁺ complex. This probably resulted from the polarization of metal ions and the structural flexion of Alisol G. The C22-O31-H76 and C18-O32-H77 of Alisol G were key groups in the interaction with c-myc DNA. Addition of metal ion, had greatly changed the c-myc DNA-binding domain of Alisol G while didn’t affect the kinetic stability of the interaction, thus facilitating the insertion of Alisol G into c-myc DNA A-T base pair. Importantly, the DG113 of c-myc DNA was important for its binding to metal ions. Together, our findings suggested that Alisol G in combination with metal ions may be an efficient and promising option for the treatment of liver cancer.     

Metal binding to bipyridine-modified PNA

Substitution of natural nucleobases in PNA oligomers with ligands is a strategy for directing metal ion incorporation to specific locations within a PNA duplex. In this study, we have synthesized PNA oligomers that contain up to three adjacent bipyridine ligands and examined the interaction with Ni2+ and Cu2+ of these oligomers and of duplexes formed from them. Variable-temperature UV spectroscopy showed that duplexes containing one terminal pair of bipyridine ligands are more stable upon metal binding than their nonmodified counterparts. While binding of one metal ion to duplexes that contain two adjacent bipyridine pairs makes the duplexes more stable, additional metal ions lower the duplex stability, with electrostatic repulsions being, most likely, an important contributor to the destabilization. UV titrations showed that the presence of several bipyridine ligands in close proximity of each other in PNA oligomers exerts a chelate effect. A supramolecular chelate effect occurs when several bipyridines are brought next to each other by hybridization of PNA duplexes. EPR spectroscopy studies indicate that even when two Cu2+ ions coordinate to a PNA duplex in which two bipyridine pairs are next to each other, the two metal-ligand complexes that form in the duplex are far enough from each other that the dipolar coupling is very weak. EXAFS and XANES show that the Ni2+-bipyridine bond lengths are typical for [Ni(bipy)2]2+ and [Ni(bipy)3]2+ complexes.     

Efficient incorporation of a copper hydroxypyridone base pair in DNA

Recently, we reported the first artificial nucleoside for alternative DNA base pairing through metal complexation (J. Org. Chem. 1999, 64, 5002-5003). In this regard, we report here the synthesis of a hydroxypyridone-bearing nucleoside and the incorporation of a neutral Cu(2+)-mediated base pair of hydroxypyridone nucleobases (H-Cu-H) in a DNA duplex. When the hydroxypyridone bases are incorporated into the middle of a 15 nucleotide duplex, the duplex displays high thermal stabilization in the presence of equimolar Cu(2+) ions in comparison with a duplex containing an A-T pair in place of the H-H pair. Monitoring temperature dependence of UV-absorption changes verified that a Cu(2+)-mediated base pair is stoichiometrically formed inside the duplex and dissociates upon thermal denaturation at elevated temperature. In addition, EPR and CD studies suggested that the radical site of a Cu(2+) center is formed within the right-handed double-strand structure of the oligonucleotide. The present strategy could be developed for controlled and periodic spacing of neutral metallobase pairs along the helix axis of DNA.     

Amino acids attached to 2'-amino-LNA: synthesis and excellent duplex stability

The synthesis of 2'-amino-LNA (the 2'-amino derivative of locked nucleic acid) has opened up a number of exciting possibilities with respect to modified nucleic acids. While maintaining the excellent duplex stability inferred by LNA-type oligonucleotides, the nitrogen in the 2'-position of 2'-amino-LNA monomers provides an excellent handle for functionalisation. Herein, the synthesis of amino acid functionalised 2'-amino-LNA derivatives is described. Following ON synthesis, a glycyl unit attached to the N2'-position of 2'-amino-LNA monomers was further acylated with a variety of amino acids. On binding to DNA/RNA complements, the modified ONs induce a marked increase in thermal stability, which is particularly apparent in a buffer system with a low salt concentration. The increase in thermal stability is thought to be caused, at least in part, by decreased electrostatic repulsion between the negatively charged phosphate backbones when positively charged amino acid residues are appended. Upon incorporation of more than one 2'-amino-LNA modification, the effects are found to be nearly additive. For comparison, 2'-amino-LNA derivatives modified with uncharged groups have been synthesised and their effect on duplex thermal stability likewise investigated.     

Metal-salen-base-pair complexes inside DNA: complexation overrides sequence information

Two isomeric salicylic aldehyde nucleobases have been prepared and incorporated into various DNA duplexes. Reaction with ethylenediamine leads to formation of the well-known salen ligand inside the DNA double helix. Addition of transition-metal ions such as Cu(2+), Mn(2+), Ni(2+), Fe(2+), or VO(2+) results in the formation of metal-salen-base-pair complexes, which were studied by using UV and circular dichroism (CD) spectroscopy. HPLC and ESI mass spectrometric measurements reveal an unusually high stability of the DNA-metal system. These metal-salen complexes act as interstrand cross-links and thereby lead to a strong stabilization of the DNA duplexes, as studied by thermal de- and renaturing experiments. Complex formation is strong enough to override sequence information even when the preorganization of the ligand precursors is unfavorable and the DNA duplex is distorted by the metal complexation. Furthermore, melting-point studies show that the salen complex derived from ligand 2 fits better into the DNA duplex, in accordance with results obtained from the crystal structure of the corresponding copper-salen complex 8.     

N-methylpiperazinocarbonyl-2',3'-BcNA and 4'-C-(N-methylpiperazino)methyl-DNA: introduction of basic functionalities facing the major groove and the minor groove of a DNA:DNA duplex

Piperazino-functionalized 2',3'-BcNA and 4'-C-hydroxymethyl-DNA are appropriate molecular architectures for the introduction of basic functionalities facing the major groove and the minor groove of nucleic acid duplexes, respectively. 4'-C-(N-Methylpiperazino)methyl-DNA monomers induce significantly increased thermal stability of a DNA:DNA duplex.     

Effect of metal ions (Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) and water coordination on the structure of glycine and zwitterionic glycine

Interactions between metal ions and amino acids are common both in solution and in the gas phase. Here, the effect of metal ions and water on the structure of glycine is examined. The effect of metal ions (Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) and water on structures of Gly.Mn+(H2O)m and GlyZwitt.Mn+(H2O)m (m = 0, 2, 5) complexes have been determined theoretically by employing the hybrid B3LYP exchange-correlation functional and using extended basis sets. Selected calculations were carried out also by means of CBS-QB3 model chemistry. The interaction enthalpies, entropies, and Gibbs energies of eight complexes Gly.Mn+ (Mn+ = Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) were determined at the B3LYP density functional level of theory. The computed Gibbs energies DeltaG degrees are negative and span a rather broad energy interval (from -90 to -1100 kJ mol(-1)), meaning that the ions studied form strong complexes. The largest interaction Gibbs energy (-1076 kJ mol(-1)) was computed for the NiGly2+ complex. Calculations of the molecular structure and relative stability of the Gly.Mn+(H2O)m and GlyZwitt.Mn+(H2O)m (Mn+ = Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+; m = 0, 2, and 5) systems indicate that in the complexes with monovalent metal cations the most stable species are the NO coordinated metal cations in non-zwitterionic glycine. Divalent cations Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+ prefer coordination via the OO bifurcated bonds of the zwitterionic glycine. Stepwise addition of two and five water molecules leads to considerable changes in the relative stability of the hydrated species. Addition of two water molecules at the metal ion in both Gly.Mn+ and GlyZwitt.Mn+ complexes reduces the relative stability of metallic complexes of glycine. For Mn+ = Li+ or Na+, the addition of five water molecules does not change the relative order of stability. In the Gly.K+ complex, the solvation shell of water molecules around K+ ion has, because of the larger size of the potassium cation, a different structure with a reduced number of hydrogen-bonded contacts. This results in a net preference (by 10.3 kJ mol(-1)) of the GlyZwitt.K+H2O5 system. Addition of five water molecules to the glycine complexes containing divalent cations Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+ results in a net preference for non-zwitterionic glycine species. The computed relative Gibbs energies are quite high (-10 to -38 kJ mol(-1)), and the NO coordination is preferred in the Gly.Mn+(H2O)5 (Mn+ = Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) complexes over the OO coordination.