Metal-DNA Complexes Research Articles

Regium-π Bonds Involving Nucleobases: Theoretical Study and Biological Implications.

In this study, we provide crystallographic (Protein Data Bank (PDB) inspection) and theoretical (RI-MP2/def2-TZVP//PBE0-D3/def2-SVP level of theory) evidence of the involvement of nucleobases in Regium-π bonds (RgBs). This noncovalent interaction involves an electrophilic site located on an element of group 11 (Cu, Ag, and Au) and an electron-rich species (lone pair, LP donor, or π-system). Concretely, an initial PDB search revealed several examples where RgBs were undertaken involving DNA bases and Cu(II), Ag(I), and Au(I/III) ions. While coordination positions (mainly at the N atoms of the base) are well known, the noncovalent binding force between these counterparts has been scarcely studied in the literature. In this regard, computational models shed light on the strength and directionality properties of the interaction, which was also further characterized from a charge-density perspective using Bader's "atoms in molecules" (AIM) theory, noncovalent interaction plot (NCIplot) visual index, and natural bonding orbital (NBO) analyses. As far as our knowledge extends, this is the first time that RgBs in metal-DNA complexes are systematically analyzed, and we believe the results might be useful for scientists working in the field of nucleic acid engineering and chemical biology as well as to increase the visibility of the interaction among the biological community.

Crystal structures and identification of novel Cd2+-specific DNA aptamer.

Cadmium (Cd) is one of the most toxic heavy metals. Exposure to Cd can impair the functions of the kidney, respiratory system, reproductive system and skeletal system. Cd2+-binding aptamers have been extensively utilized in the development of Cd2+-detecting devices; however, the underlying mechanisms remain elusive. This study reports four Cd2+-bound DNA aptamer structures, representing the only Cd2+-specific aptamer structures available to date. In all the structures, the Cd2+-binding loop (CBL-loop) adopts a compact, double-twisted conformation and the Cd2+ ion is mainly coordinated with the G9, C12 and G16 nucleotides. Moreover, T11 and A15 within the CBL-loop form one regular Watson-Crick pair and stabilize the conformation of G9. The conformation of G16 is stabilized by the G8-C18 pair of the stem. By folding and/or stabilizing the CBL-loop, the other four nucleotides of the CBL-loop also play important roles in Cd2+binding. Similarly to the native sequence, crystal structures, circular dichroism spectrum and isothermal titration calorimetry analysis confirm that several variants of the aptamer can recognize Cd2+. This study not only reveals the underlying basis for the binding of Cd2+ ions with the aptamer, but also extends the sequence for the construction of novel metal-DNA complex.

Lanthanide ions induce DNA compaction with ionic specificity

Lanthanide (Ln) cations exhibit unique properties that include the ability to interact with DNA to form metal–DNA complexes, which are of great interest in medical, biological and nano-technological fields. Both experimental and theoretical studies have not completely addressed the interaction dynamics between lanthanide ions and DNA. The present study investigates the dynamics of the Ln3+–DNA interaction at the level of a single DNA molecule. Different DNA-metal complexes were produced by the addition of the five lanthanide ions, La3+, Ce3+, Pr3+, Tb3+, and Ho3+ to the DNA solutions. The binding dynamics indicated that the lanthanide cations can induce DNA compaction in a concentration and force-dependent manner. Ionic specificity was displayed in the single-molecule interaction dynamics, where, Ho3+ was found to be the most efficient lanthanide to cause DNA compaction, which was verified by the morphological characterization. The DNA molecules in the five Ln3+–DNA complex solutions were restored to their original length with different restoration speeds, by the addition of EDTA, and this further indicated that the Ho3+ ion had the strongest affinity toward DNA. We conclude that counterion correlation cannot solely explain the ion-dependent DNA compaction, and ionic specificity should be considered significant.

Construction and structure studies of DNA-bipyridine complexes as versatile scaffolds for site-specific incorporation of metal ions into DNA

The facile construction of metal–DNA complexes using ‘Click’ reactions is reported here. A series of 2′-propargyl-modified DNA oligonucleotides were initially synthesized as structure scaffolds and were then modified through ‘Click’ reaction to incorporate a bipyridine ligand equipped with an azido group. These metal chelating ligands can be placed in the DNA context in site-specific fashion to provide versatile templates for binding various metal ions, which are exchangeable using a simple EDTA washing-and-filtration step. The constructed metal–DNA complexes were found to be thermally stable. Their structures were explored by solving a crystal structure of a propargyl-modified DNA duplex and installing the bipyridine ligands by molecular modeling and simulation. These metal–DNA complexes could have wide applications as novel organometallic catalysts, artificial ribonucleases, and potential metal delivery systems.

Role of Water Molecules to the Electronic States of M-DNA

Various kinds of roles of the water molecules in the electronic states of the complexes of metal ions (M) and deoxyribonucleic acid (DNA) are reviewed. Divalent metal ions M like Fe, Mn, Zn and so on, form Metal-DNA complexes (M-DNA) with each metal ion between the bases of a base pair of DNA. The electronic states of the complexes depend on the species of ions in M-DNA. Metal ions in Fe-DNA and Mn-DNA possess 3d magnetic moments, but those in Zn-DNA do not. Interestingly, the magnetic property of the complexes, especially the magnetic interaction between the metal ions, is dominated by water molecules in the complexes. In Fe-DNA, the water molecules play a role of ligands for the iron ions, which controls the spin states of Fe3+, whereas they govern the magnetic interaction between the Mn2+ ions in Mn-DNA. In contrast, Zn-DNA has no 3d magnetic moment, but the water molecules dominate the bonding states of the Zn ions and the magnetic states of the Zn-DNA system.

Silver Arrays Inside DNA Duplexes Constructed from Silver(I)‐Mediated Pyrrolo‐dC–Pyrrolo‐dC Base Pairs

AbstractTuneable silver arrays inside DNA duplexes were constructed by multiple incorporations of pyrrolo‐dC–pyrrolo‐dC base pairs. A short array with six silver ions was built within a DNA template. The size and positioning of the array is programmable and depends on the incorporation site of the modified base pairs. Always two silver ions were captured by one pyrrolo‐dC–pyrrolo‐dC pair as confirmed by melting experiments, UV and fluorescence titration experiments as well as ESI mass spectra. The silver‐mediated pyrrolo‐dC–pyrrolo‐dC base pairs with phenyl residues in the 6‐position were significantly more stable than those containing methyl substitutions. The caged silver ions are released from duplex DNA by sodium iodide but not by chloride or bromide anions, thus indicating very high stability of the metal–DNA complex.

Specific and nonspecific bindings of alkaline-earth metal ions to guanine-quadruplex thrombin-binding aptamer DNA

Specific and nonspecific bindings of alkaline-earth metal ions to the thrombin-binding aptamer (TBA) DNA d(GGTTGGTGTGGTTGG) were studied using electrospray ionization (ESI) mass spectrometry (MS). A single-stranded DNA d(AATTAATGTAATTAA) was used as a control for nonspecific binding. Both 1:1 and 2:1 metal–DNA complexes formed in 3:1 water/isopropanol were detected with ESI-MS and their binding constants were determined by the titration method. The 1:1 binding constant (K1) of Sr2+ or Ba2+ for TBA was three orders of magnitude greater than their K1 for the control DNA, whereas K1 of Mg2+ or Ca2+ for TBA was comparable to their K1 for the control DNA. To the contrary, the second binding constant (K2) was nearly the same independent of the metal ion and DNA. To see if addition of metal ion led to a structural change in DNA, the circular dichroism (CD) spectra of DNA in ESI solvent were obtained in the presence and absence of metal ion. TBA showed characteristic bands of the chair-type guanine-quadruplex (G4) structure. Significantly, addition of Sr2+ or Ba2+ enhanced the G4 bands of TBA, but neither Mg2+ nor Ca2+ induced a change, indicating that Sr2+ and Ba2+ interact strongly with G4 TBA and stabilize it. Control DNA showed no special motif and none of the four metal ions affected its CD spectra. Binding constants and CD results suggest that only the first binding of Sr2+ and Ba2+ to G4 TBA is specific and the first binding of Mg2+ and Ca2+ as well as the second binding of all four metal ions are nonspecific. The specific and nonspecific bindings of alkaline-earth metal ions to G4 TBA are further rationalized in terms of ionic radius, coordination number, and Gibbs free energy of dehydration of the metal ion.

Strong Correlations in Highly Electron-Doped Zn(II)-DNA Complexes

We present spectroscopic measurements on the first example of a chemically electron-doped metal-DNA complex. We show that a doping level as high as the stoichiometric limit of one electron per base pair can be achieved. The doped unpaired electrons occupy lowest unoccupied molecular orbital levels of the nucleobases as detected with electron spin resonance and x-ray absorption near edge structure measurements. Delocalization and strong correlations between the unpaired electrons are evident from a temperature-independent spin susceptibility and a microwave conductivity above 100 K.

Effects of mercury(ii) on structural properties, electronic structure and UV absorption spectra of a duplex containing thymine–mercury(ii)–thymine nucleobase pairs

Structural properties, electronic structure and UV absorption spectra of mercury(ii) mediated metal-DNA complex, thymine-mercury(ii)-thymine base pair (T-Hg(II)-T), were theoretically and computationally investigated along with experimental data [Ono et al., J. Am. Chem. Soc., 2006, 128(7), 2172-2173]. The results were obtained by density functional theory (DFT) calculations for ground state and time-dependent DFT (TD-DFT) calculations for excited states associated with the polarized continuum model (PCM) in order to account for the bulk solvent effect. The LUMO of T-Hg(II)-T was stabilized due to the presence of Hg(II) since an unoccupied 6p orbital interacted with the 2p orbitals of thymine N3 atoms in the same way as in a pi-conjugated system. Thus, excitations in T-Hg(II)-T involve transitions qualitatively different from those of the thymine-thymine mismatch base pair (T-T). Since conventional DFT functionals lack correct description of dispersion forces, a method previously developed in our research group which combines DFT and a van der Waals correction functional was introduced to study multiple stacking nucleobase pairs. Based on the evaluated distance and the interaction energy between two stacking nucleobase pairs, the selective capturing of Hg(II) ion by T-T compared to other metal ions is explained. The calculated UV absorption spectra of multiple stacking nucleobase pairs reproduced the decrease of absorption around 260 nm and the red-shift of the main peak experimentally observed in the presence of Hg(II) ion. Detailed analysis of the electronic structure revealed that the metal-metal interaction between two Hg(II) in multiple stacking T-Hg(II)-T is the origin of the significant changes in UV absorption spectra.

Heavy metal ions affect the activity of DNA glycosylases of the Fpg family

Prokaryotic enzymes formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease VIII (Nei) and their eukaryotic homologs NEIL1, NEIL2, and NEIL3 define the Fpg family of DNA glycosylases, which initiate the process of repair of oxidized DNA bases. The repair of oxidative DNA lesions is known to be impaired in vivo in the presence of ions of some heavy metals. We have studied the effect of salts of several alkaline earth and transition metals on the activity of Fpg-family DNA glycosylases in the reaction of excision of 5,6-dihydrouracil, a typical DNA oxidation product. The reaction catalyzed by NEIL1 was characterized by values K(m) = 150 nM and k(cat) = 1.2 min(-1), which were in the range of these constants for excision of other damaged bases by this enzyme. NEIL1 was inhibited by Al3+, Ni2+, Co2+, Cd2+, Cu2+, Zn2+, and Fe2+ in Tris-HCl buffer and by Cd2+, Zn2+, Cu2+, and Fe2+ in potassium phosphate buffer. Fpg and Nei, the prokaryotic homologs of NEIL1, were inhibited by the same metal ions as NEIL1. The values of I(50) for NEIL1 inhibition were 7 microM for Cd2+, 16 microM for Zn2+, and 400 microM for Cu2+. The inhibition of NEIL1 by Cd2+, Zn2+, and Cu2+ was at least partly due to the formation of metal-DNA complexes. In the case of Cd2+ and Cu2+, which preferentially bind to DNA bases rather than phosphates, the presence of metal ions caused the enzyme to lose the ability for preferential binding to damaged DNA. Therefore, the inhibition of NEIL1 activity in removal of oxidative lesions by heavy metal ions may be a reason for their co-mutagenicity under oxidative stress.

Conformational Tuning of Magnetic Interactions in Metal–DNA Complexes

The alignment of Cu(2+) ions along a modified DNA helix is studied with either hydroxypyridone (H) or bis(salicylaldehyde)ethylenediamine (S-en) metalated base pairs (MBPs). The conformational motion of H-MBP leads to the interlinking of the H-MBPs by an extended Cu-O network that is ferromagnetic, whereas the conformational freezing of the S-en-MBP leads to an ordered pairwise-stacked arrangement that is weakly antoferrimagnetic.

Conformational Tuning of Magnetic Interactions in Metal–DNA Complexes

AbstractDie Anordnung von Cu2+‐Ionen entlang einer modifizierten DNA‐Helix wurde studiert; dabei kamen entweder über Hydroxypyridon (H) oder Bis(salicylaldehyd)ethylendiamin (S‐en) metallierte Basenpaare (MBPs) zum Einsatz. Die bewegliche Konformation von H‐MBP führt zur Verknüpfung der H‐MBPs durch ein ferromagnetisches Cu‐O‐Netzwerk, die festgelegte Konformation von S‐en‐MBP resultierte dagegen in paarweiser Stapelung und schwach antiferromagnetischen Eigenschaften.magnified image

Electrochemical and AFM evaluation of hazard compounds–DNA interaction

The evaluation of the interaction of hazard compounds, divalent cations Pb, Cd, Ni and Pd, with double-stranded DNA (dsDNA), forming a metal–DNA complex, was studied by atomic force microscopy (AFM) and differential pulse voltammetry (DPV) on two carbon electrode surfaces, highly oriented pyrolytic graphite (HOPG) and glassy carbon (GC). The electrochemical behaviour of these metal–DNA complexes was related to the different adsorption patterns and conformational changes obtained by the AFM images on the HOPG surface. The dsDNA interaction was specific with each metal cation, inducing structural changes in the B-DNA structure, local denaturation of the double helix and oxidative damage. AFM images showed an increase of the electrode surface coverage for lead, cadmium and nickel DNA complexes. For cadmium and nickel–DNA complexes oxidative damage to DNA was electrochemically detected for the concentrations studied. Palladium interaction with dsDNA induced condensation of the dsDNA secondary structure, which led to the aggregation of helixes forming very compact and thick filaments in the network film. The voltammetric data for the palladium–DNA complex showed a sharp decrease of the guanosine and adenosine oxidation peak currents, consistent with the AFM results of DNA condensation in the presence of palladium, but no DNA oxidative damage was detected for the range of concentrations used.

Pb EXAFS studies on DNA quadruplexes: identification of metal ion binding site.

Nucleic acid quadruplexes are composed of guanine quartets stabilized by specific metal ions. X-ray diffraction can provide high-resolution information on the structure and metal binding properties of quadruplexes, but only if they can be crystallized. NMR can provide detailed information on the solution structure of such quadruplexes but little quantitative data concerning the metal binding site. Here we apply extended X-ray absorption fine structure (EXAFS) measurements to characterize the metal ion binding site, in frozen solution, of the unimolecular quadruplex formed by the thrombin binding aptamer, d(G(2)T(2)G(2)TGTG(2)T(2)G(2)) (TBA), in the presence of Pb(2+) ions. The Pb L(III) -edge X-ray absorption spectrum of this metal-DNA complex is very similar to that we obtain for a Pb(2+)-stabilized quartet system of known structure constructed from a modified guanine nucleoside (G1). The Fourier transforms of the Pb(2+) complexes with both TBA and G1 show a first-shell interaction at about 2.6 A, and a weaker, broader shell at 3.5-4.0 A. Quantitative analysis of the EXAFS data reveals the following: (i) very close agreement between interatomic distances at the metal coordination site for the Pb(2+)-G1 complex determined by EXAFS and by X-ray crystallography; (ii) similarly close agreement between interatomic distances measured by EXAFS for the Pb(2+)-G1 and Pb(2+)-TBA complexes. These results provide strong evidence for binding of the Pb(2+) ion in the region between the two quartets in the Pb(2+)-TBA complex, coordinated to the eight surrounding guanine O6 atoms. The specific binding of Pb(2+) to DNA examined here may be relevant to the genotoxic effects of this environmentally important heavy metal. Furthermore, these results demonstrate the utility of EXAFS as a method for quantitative characterization of specific metal binding sites in nucleic acids in solution.

Calorimetric and spectroscopic studies on the poly[d(GA).d(CT)] structural polymorphism induced by zinc.

The interaction of zinc (II) with poly[d(GA).d(CT)] and salmon testes DNA has been investigated by Differential Scanning Calorimetry (DSC) and Circular Dichroism (CD). We have detected and energetically characterized the existence of two different structural forms in poly[d(GA).d(CT)] which behave differently during a DSC experiment. The overall melting of DNA shows two calorimetric transitions at different temperatures. Moreover, the presence of zinc, at an input ratio of ion to nucleotide (r) above two, renders a complex DSC profile which is characterized by a negative enthalpy transition. Besides, the low-temperature transition observed in the presence of zinc is practically reversible after re-cooling/re-heating cycles. Nevertheless, the high-temperature transition characterized by a negative delta H degree cal does not appear in re-heating experiments, and remains stable below 100 degrees C. A calorimetric negative enthalpy transition is also found using salmon DNA in the presence of zinc ions. It seems that the combination of a temperature effect and zinc binding might induce the production of a stable metal-DNA complex, which can also be detected by changes in some bands in the CD profiles. The experimental results show that the presence of DNA structures and binding processes involving a negative calorimetric enthalpy contribution might be more widespread than previously reckoned.

Interaction of aluminum species with deoxyribonucleic acid.

Interactions of aluminum with deoxyribonucleic acid (DNA) have been studied by thermal denaturation, circular dichroism, and fluorescent dye binding; a pH- and concentration-dependent alteration in the interaction of aluminum with DNA was observed. Three distinguishable complexes are produced when DNA is denaturated at pH 5.0-7.5 and in aluminum to DNA mole ratios of 0-0.7. Complex I appears at neutral pH and stabilizes a portion of DNA. Complex II is observed at acidic pH, destabilizes a fraction of the DNA double-helical molecule, and produces intrastrand cross-links. Complex III occurs at all pHs, is maximal at intermediate pH values, and is characterized by a noncooperative melting profile and cross-linking at low pH (less than 6.0). The DNA in complexes II and III can be renatured by treatment with either ethylenediaminetetraacetic acid (EDTA) or a high concentration of sodium chloride. The properties of complexes I and II are consistent with what could be expected for DNA complexes of Al(OH)2+ and Al3+, respectively. Complex III has intermediate properties that are consistent with a structure in which both ions bind the DNA simultaneously. The characteristics of complex III depend on the ratio of Al3+/Al(OH)2+ in solution. Aluminum-DNA complexes differ from other metal-DNA complexes in that melting profiles under many conditions are biphasic. Apparently more than one form of DNA can exist at any time in the presence of aluminum. The different DNA-aluminum complexes, which arise from the multiple species of aluminum in aqueous solution, lead to a variety of reactions with DNA.

Effects of metal ions on radical formation in gamma-irradiated DNA in the solid state.

The effects of metal ions on the formation of radicals produced by $gamma$ radiolysis of DNA in vacuo were studied by esr and hydrogen-transfer measurements. At metal to nucleotide ratios of 1 : 10, a three- to tenfold decrease of the esr signal due to carbon was observed for transition metals such as Cr$sup 3+$, Fe$sup 3+$, Fe$sup 2+$, Ni$sup 2+$, and Co$sup 2+$, and smaller decreases (by 25 to 40 percent) were seen for paramagnetic rare earths (Eu$sup 3+$, Yb$sup 3+$, and Sm$sup 3+$). These effects were independent of dose and temperature (77 to 298$sup 0$K). The diamagnetic ions Mg$sup 2+$, Zn$sup 2+$, Cd$sup 2+$, Ag$sup +$, La$sup 3+$, and Lu$sup 3+$ had no effect; however, Ce$sup 4+$, Pb$sup 2+$, Sn$sup 4+$, and Hg$sup 2+$ decreased the radical yield by 10 to 60 percent. At metal to nucleotide ratios of 1:100, the radical yield was decreased twofold for Cr$sup 3-$, Cu$sup 2+$, and Fe$sup 2+$, about 30 percent for Mn$sup 2+$, Ni$sup 2+$, and Fe$sup 3+$ and less than 10 percent for Co$sup 2+$. From measurements of the power-saturation of the carbon signal for the 1:100 metal-DNA complexes, it can be inferred that the decrease of the esr signalsmore » is not due to spin-spin interactions between carbon radicals and paramagnetic ions. For the 1:10 metal-DNA complexes, spin-spin interactions may contribute to signal reduction. However, these results correlate with measurements of the radiation-induced hydrogen transfer, which can be explained by assuming a decreased radical yield; 1:10 complexes of Ni$sup 2+$ with adenine, polyadenylic acid, dextran, poly-DL-alanine, and poly-L-glutamic acid decreased the radical yield by 60 to 70 percent, but no effect was observed for thymine and thymidine. It appears that the metal ions act by quenching excited states and/or by charge scavenging. (auth)« less