Metal Ion-nucleic Acid Interactions Research Articles

Specific binding of Ag+ to central C[sbnd]C mismatched base pair but not terminal C[sbnd]C pair in duplex DNA

Metal ion-nucleic acid interactions are important for their contribution in structure formation and their potential applications in nanotechnology. Hg2+ and Ag+ bind to T–T and CC mismatched base pairs, respectively, at the center of duplex DNA to form T–Hg–T and C–Ag–C. Although primer-extension by DNA polymerases with Hg2+ incorporated thymidine 5′-triphosphate to form T–Hg–T, the same reaction with Ag+ did not incorporate deoxycytidine 5′-triphosphate to form C–Ag–C. Here, isothermal titration calorimetric analyses to examine the effect of CC position in duplex DNA on Ag+ binding demonstrated that Ag+ did not bind to the terminal CC base pair in duplex, but it bound to the central CC base pair in duplex at 1:1 molar ratio with 9 × 105 M–1 binding constant. Ag+ did not bind to the terminal and central C–A, C–G, and C–T base pairs in duplex. These findings are useful for developing efficient metal-mediated base pair formation in nanotechnology.

Importance of isothermal titration calorimetry for the detection of the direct binding of metal ions to mismatched base pairs in duplex DNA.

Metal ion-nucleic acid interactions contribute substantially to the structure and biological activity of nucleic acids and have a wide range of potential applications in nanotechnology. In this study, we examined the interactions between metal ions and mismatched base pairs in duplex DNA to reveal the underlying molecular mechanism. UV melting analyses showed that the melting temperature (Tm) of a 21-base pair duplex DNA with each of the C-A, C-C and C-T mismatched base pairs increased upon the addition of Ag+. However, isothermal titration calorimetry (ITC) demonstrated that Ag+ only bound to the C-C mismatched base pair of the duplex DNA to form C-Ag-C bonds, without binding to the C-A and C-T mismatches. These results showed that Tm increased even when metal ions did not bind to the mismatched base pairs of the duplex DNA. Although the increase in Tm upon the addition of the metal ions is often used to detect metal ion binding to mismatched base pairs of duplex DNA, these results indicated that UV melting analyses are unable to detect the direct binding of metal ions to the mismatched base pairs. Because ITC analyses directly detect the heat derived from metal ion binding to mismatched base pairs of duplex DNA, we concluded that this may be an effective detection approach.

Predicting Monovalent Ion Correlation Effects in Nucleic Acids.

Ion correlation and fluctuation can play a potentially significant role in metal ion–nucleic acid interactions. Previous studies have focused on the effects for multivalent cations. However, the correlation and fluctuation effects can be important also for monovalent cations around the nucleic acid surface. Here, we report a model, gMCTBI, that can explicitly treat discrete distributions of both monovalent and multivalent cations and can account for the correlation and fluctuation effects for the cations in the solution. The gMCTBI model enables investigation of the global ion binding properties as well as the detailed discrete distributions of the bound ions. Accounting for the ion correlation effect for monovalent ions can lead to more accurate predictions, especially in a mixed monovalent and multivalent salt solution, for the number and location of the bound ions. Furthermore, although the monovalent ion-mediated correlation does not show a significant effect on the number of bound ions, the correlation may enhance the accumulation of monovalent ions near the nucleic acid surface and hence affect the ion distribution. The study further reveals novel ion correlation-induced effects in the competition between the different cations around nucleic acids.

Force Field for Mg(2+), Mn(2+), Zn(2+), and Cd(2+) Ions That Have Balanced Interactions with Nucleic Acids.

Divalent metal ions are of fundamental importance to the function and folding of nucleic acids. Divalent metal ion-nucleic acid interactions are complex in nature and include both territorial and site specific binding. Commonly employed nonbonded divalent ion models, however, are often parametrized against bulk ion properties and are subsequently utilized in biomolecular simulations without considering any data related to interactions at specific nucleic acid sites. Previously, we assessed the ability of 17 different nonbonded Mg(2+) ion models to reproduce different properties of Mg(2+) in aqueous solution including radial distribution functions, solvation free energies, water exchange rates, and translational diffusion coefficients. In the present work, we depart from the recently developed 12-6-4 potential models for divalent metal ions developed by Li and Merz and tune the pairwise parameters for Mg(2+), Mn(2+), Zn(2+), and Cd(2+) binding dimethyl phosphate, adenosine, and guanosine in order to reproduce experimental site specific binding free energies derived from potentiometric pH titration data. We further apply these parameters to investigate a metal ion migration previously proposed to occur during the catalytic reaction of the hammerhead ribozyme. The new parameters are shown to be accurate and balanced for nucleic acid binding in comparison with available experimental data and provide an important tool for molecular dynamics and free energy simulations of nucleic acids where these ions may exhibit different binding modes.

Thermodynamic and structural properties of the specific binding between Ag+ ion and C:C mismatched base pair in duplex DNA to form C–Ag–C metal-mediated base pair

Metal ion-nucleic acid interactions have attracted considerable interest for their involvement in structure formation and catalytic activity of nucleic acids. Although interactions between metal ion and mismatched base pair duplex are important to understand mechanism of gene mutations related to heavy metal ions, they have not been well-characterized. We recently found that the Ag(+) ion stabilized a C:C mismatched base pair duplex DNA. A C-Ag-C metal-mediated base pair was supposed to be formed by the binding between the Ag(+) ion and the C:C mismatched base pair to stabilize the duplex. Here, we examined specificity, thermodynamics and structure of possible C-Ag-C metal-mediated base pair. UV melting indicated that only the duplex with the C:C mismatched base pair, and not of the duplexes with the perfectly matched and other mismatched base pairs, was specifically stabilized on adding the Ag(+) ion. Isothermal titration calorimetry demonstrated that the Ag(+) ion specifically bound with the C:C base pair at 1:1 molar ratio with a binding constant of 10(6) M(-1), which was significantly larger than those for nonspecific metal ion-DNA interactions. Electrospray ionization mass spectrometry also supported the specific 1:1 binding between the Ag(+) ion and the C:C base pair. Circular dichroism spectroscopy and NMR revealed that the Ag(+) ion may bind with the N3 positions of the C:C base pair without distorting the higher-order structure of the duplex. We conclude that the specific formation of C-Ag-C base pair with large binding affinity would provide a binding mode of metal ion-DNA interactions, similar to that of the previously reported T-Hg-T base pair. The C-Ag-C base pair may be useful not only for understanding of molecular mechanism of gene mutations related to heavy metal ions but also for wide variety of potential applications of metal-mediated base pairs in various fields, such as material, life and environmental sciences.

REVIEW: INTERACTIONS OF METAL IONS WITH NUCLEIC ACIDS AND THEIR SUBUNITS. AN ELECTROCHEMICAL APPROACH

Abstract Different electrochemical methods (differential pulse polarography, sweep voltammetry, alternating current voltammetry, chronocoulometry, cyclic voltammetry) can be used to investigate the interactions of metal ions such as osmium tetroxide, platinum complexes, Cu(II), Ni(II), Zn(II), Cd(II), Pb(II) and Eu(III) with DNA, t-RNA and their subunits. Modern electrochemical methods can detect very small perturbations in a double-helical structure as well as the behavior of single stranded (denatured) fragments of nucleic acids. The effectiveness of polarographic methods is comparable to enzymatic techniques which use specific nucleases. The polarographic data can also be used for the quantitative evaluation of the metal ion nucleic acid interactions (e.g., to calculate the association or stability constants and the number of binding sites). Some topics concerning these problems as well as general aspects of metal-nucleic acid interactions are discussed in this review.

From cisplatin to artificial nucleases--the role of metal ion-nucleic acid interactions in biology.

Metal ions and metal coordination compounds bind to nucleic acids in a variety of ways, ranging from weak electrostatic interactions via hydrogen bonding and/or van der Waals forces to strong covalent binding. Metal ions naturally take part in the formation and the degradation of nucleic acids, and the propensity of certain metal coordination compounds to bind to nucleic acids, notably DNA, is exploited in cancer chemotherapy. Moreover, metal compounds have a wide potential as chemical probes for nucleic acid structures and as tools for nucleic acid processing.

Metal ion-nucleic acid interactions: II. A method for the fractionation of Escherichia coli RNA's into transfer RNA and ribosomal RNA's using Zn 2+ or Cd 2+ as precipitant

In acetate buffer (pH 4.5) at 4°, Zn 2+, at a concentration of 0.2 M, fractionates the total RNA of Escherichia coli, prepared according to the hot phenol method, into rRNA's and tRNA. A similar fractionation is achieved with 0.1 M Cd 2+ at pH 5.0. The metal ion-insoluble and metal ion-soluble fractions were characterized by means of sucrose density gradient centrifugation, analytical ultracentrifugation, gel filtration on Sephadex G-150 and by measurement of amino acid-acceptor activity. The metal ion-insoluble fraction contained the two rRNA's, which had sedimentation coefficients of 21 S and 14 S, and was free from amino acid-acceptor activity. The metal ion-soluble fraction contained only tRNA, which had a sedimentation coefficient of 4 S, and had amino acid-acceptor activity which was comparable with that of “standard tRNA” obtained by gel filtration of total RNA. The melting curve of this fraction was indistinguishable from that of standard tRNA. Fractionation into rRNA's and tRNA could not be achieved with Cu 2+.

Metal ion-nucleic acid interactions. I. A method for the fractionation of rat liver ribonucleic acids into transfer ribonucleic acid and ribosomal ribonucleic acids using Zn-II as a precipitant.

Metal ion-nucleic acid interactions. I. A method for the fractionation of rat liver ribonucleic acids into transfer ribonucleic acid and ribosomal ribonucleic acids using Zn-II as a precipitant.