Theoretical Study of the Stability of the DNA Duplexes Modified by a Series of Hydrophobic Base Analogues

The geometries of a 13 mer of a DNA double helix (5′‐GCGTAC A CATGCG‐3′) were determined by molecular dynamics simulations using a Cornell et al. empirical force field. The bases in the central base pair (shown in bold) were replaced (one or both) by a series of hydrophobic base analogues (phenyl, biphenyl, phenylnaphathalene, phenylanthracene and phenylphenanthrene). Due to the large fluctuations of the systems, an average geometry could not be determined. The interaction energies of the Model A, which consisted of three central steps of a duplex without a sugar phosphate backbone, taken from molecular dynamics simulations (geometry sampled every 1 ps), were calculated by the self‐consistent charge density functional based tight‐binding (SCC‐DFTB‐D) method and were subsequently averaged. The higher the stability of the systems the higher the aromaticity of the base analogues. To estimate the desolvation energy of the duplex, the COSMO continuum solvent model was used and the calculations were provided on a larger model, Model B (the three central steps of the duplex with a sugar phosphate backbone neutralised by H atoms), taken from molecular dynamics simulations (geometry sampled every 200 ps) and subsequently averaged. The selectivity of the base analogue pairs was ascertained (Model B) by including the desolvation energy and the interaction energy of both strands, as determined by the SCC‐DFTB‐D method. The highest selectivity was found for a phenylphenanthrene. Replacing the nucleic acid bases with a base analogue leads to structural changes of the central pair. Only with the smallest base analogues (phenyl) does the central base pair stay planar. When passing to larger base analogues the central base pair is usually stacked.     

DNA Switches: From Principles to Applications

The base sequence of nucleic acid encodes structural and functional properties into the biopolymer. Structural information includes the formation of duplexes, G‐quadruplexes, i‐motif, and cooperatively stabilized assemblies. Functional information encoded in the base sequence involves the strand‐displacement process, the recognition properties by aptamers, and the catalytic functions of DNAzymes. This Review addresses the implementation of the information encoded in nucleic acids to develop DNA switches. A DNA switch is a supramolecular nucleic acid assembly that undergoes cyclic, switchable, transitions between two distinct states in the presence of appropriate triggers and counter triggers, such as pH value, metal ions/ligands, photonic and electrical stimuli. Applications of switchable DNA systems to tailor switchable DNA hydrogels, for the controlled drug‐release and for the activation of switchable enzyme cascades, are described, and future perspectives of the systems are addressed.     

Role of electron correlation in the quantum-mechanical calculations of the coulomb interaction energy in the DNA base pairs

The intermolecular electronic correlation contributions to the Coulomb component of the nucleic acid base interaction energy are estimated. The Coulomb energy is evaluated with the use of atomic monopoles, which are determined from the π-electronic densities calculated by the SCF method and by employing partially or completely optimized APSG wave functions. When the correlation is thus taken into account, a systematic decrease in atomic charges occurs; this effect is considerable only if an optimized orbital set is used. As a result, the Coulomb interaction energy due to the π-electronic atoms decreases from ?1.13 to ?0.85 kcal/mol for the AT pair and from ?7.15 to ?4.61 kcal/mol for the GC pair.     

On the role of mercury in the non-covalent stabilisation of consecutive U-Hg(II)-U metal-mediated nucleic acid base pairs: metallophilic attraction enters the world of nucleic acids

Metal atoms with a closed-shell electronic structure and positive charge as for example the Au(I), Pt(II), Ag(I), Tl(I) or Hg(II) atoms do not in some compounds repel each other due to the so-called metallophilic attraction (P. Pyykk?, Chem. Rev., 1997, 97, 597-636). Here we highlight the role of the Hg(II)Hg(II) metallophilic attraction between the consecutive metal-mediated mismatched base pairs of nucleic acids. Usually, the base stacking dominates the non-covalent interactions between steps of native nucleic acids. In the presence of metal-mediated base pairs these non-covalent interactions are enriched by the metal-base interactions and the metallophilic attraction. The two interactions arising due to the metal linkage of the mismatches were found in this study to have a stabilizing effect on nucleic acid structure. The calculated data are consistent with recent experimental observations. The stabilization due to the metallophilic attraction seems to be a generally important concept for the nucleic acids containing heavy metals with short contacts.     

Functional Xeno Nucleic Acids for Biomedical Application

Functional nucleic acids(FNAs) refer to a type of oligonucleotides with functions over the traditional genetic roles of nucleic acids, which have been widely applied in screening, sensing and imaging fields. However, the potential application of FNAs in biomedical field is still restricted by the unsatisfactory stability, biocompatibility, biodistribution and immunity of natural nucleic acids(DNA/RNA). Xeno nucleic acids(XNAs) are a kind of nucleic acid analogues with chemically modified sugar groups that possess improved biological properties, including improved biological stability, increased binding affinity, reduced immune responses, and enhanced cell penetration or tissue specificity. In the last two decades, scientists have made great progress in the research of functional xeno nucleic acids, which makes it an emerging attractive biomedical application material. In this review, we summarized the design of functional xeno nucleic acids and their applications in the biomedical field.     

Conformational analysis of double-helical polynucleotides

The intramolecular interaction energy of the regular double-helical polynucleotide as a function of variables that determine the mutual position of base pairs and sugar pucker was calculated using atom–atom potentials. The calculations showed the existence of two valley-like regions with minimal values on the energetic surface. One of them corresponds to the A family of nucleic acids, the other to the B family. The points that correspond to the models constructed by means of x-ray data are placed in a conformational space near the lines that describe the position of the bottom of the valleys.     

Study on suitability of KOD DNA polymerase for enzymatic production of artificial nucleic acids using base/sugar modified nucleoside triphosphates

Recently, KOD and its related DNA polymerases have been used for preparing various modified nucleic acids, including not only base-modified nucleic acids, but also sugar-modified ones, such as bridged/locked nucleic acid (BNA/LNA) which would be promising candidates for nucleic acid drugs. However, thus far, reasons for the effectiveness of KOD DNA polymerase for such purposes have not been clearly elucidated. Therefore, using mutated KOD DNA polymerases, we studied here their catalytic properties upon enzymatic incorporation of nucleotide analogues with base/sugar modifications. Experimental data indicate that their characteristic kinetic properties enabled incorporation of various modified nucleotides. Among those KOD mutants, one achieved efficient successive incorporation of bridged nucleotides with a 2'-ONHCH?CH?-4' linkage. In this study, the characteristic kinetic properties of KOD DNA polymerase for modified nucleoside triphosphates were shown, and the effectiveness of genetic engineering in improvement of the enzyme for modified nucleotide polymerization has been demonstrated.     

Functional tuning of nucleic acids by chemical modifications: tailored oligonucleotides as drugs,devices, and diagnostics

Chemical modifications of nucleic acids present vast opportunities for extending the functions and properties of these biomolecules. In general, efforts invested in this direction pertain to the introduction of reactive functional groups for further derivatizations of oligonucleotides with numerous reporter groups and for equipping nucleic acids with catalytic chemical moieties. This review deals with representative chemical modifications in the nucleobases, sugars, and the phosphate ester backbone and their application from novel catalytic RNA selection to nucleic acid-based biosensors.     

Progress on Detection of Metals Ions by Functional Nucleic Acids Biosensor

Functional nucleic acids are natural or artificial nucleic acid sequences with specific functions and special structures. A part of metal ions are essential trace elements of human health, but excessive metal ions will be harmful to human health. The functional nucleic acids are widely used for detection of metal ions because of its advantages such as easy modification, low price, high stability and strong specificity. This paper detailed the interaction between functional nucleic acids and metal ions, mainly including cutting type, link type, metal ion-mediated base pairing, click chemistry type, conformational change type, and other types. The biosensors based on the combination of functional nucleic acid with different signal output were then introduced. Finally, the research significance and existing problems of functional nucleic acid for metal ion detection were discussed. The future development trends and applications of functional nucleic acid biosensor were prospected.     

The Radical Cationic Repair Pathway of Cyclobutane Pyrimidine Dimer: The Effect of Sugar‐Phosphate Backbone

Radical cationic repair process of cis–syn thymine dimer has been investigated when (1) sugar‐phosphate backbones were substituted by hydrogen atoms, (2) phosphate group was substituted by two hydrogen atoms each on a sugar ring and (3) sugar‐phosphate backbone was taken into account. The effect of the interactions between N1 and N1′ lone pairs and the C6‐C6′ antibonding orbital are the most important evidences for the cleavage of the C6‐C6′ bond in the first step of radical cationic repair mechanism in the absence of the sugar‐phosphate backbone. The impact of the N1 and N1′ lone pairs on the C6‐C6′ bond cleavage decreases and the energy barrier of the cleavage of that bond significantly increases in the presence of the deoxynucleoside sugars and the sugar‐phosphate backbone.     

Toward a full characterization of nucleic acid components in aqueous solution: simulations of nucleosides

The eight nucleoside constituents of nucleic acids were simulated for 50 ns in explicit water with molecular dynamics. This provides equilibrium populations of the torsional degrees of freedom, their kinetics of interconversion, their couplings, and how they are influenced by water. This is important, given that a full and quantitative characterization of the nucleosides in aqueous solution by experimental means has been elusive, despite immense efforts in that direction. It is with the anti/syn equilibrium that the simulations are most complementary to experiment, by accessing directly the influence of the sugar type, sugar pucker, and base on the anti/syn populations. The glycosidic torsion distributions in the anti conformation are strongly affected by water and depart from the corresponding X-ray modal values and the associated energy minima in vacuo. Water also preferentially stabilizes some sugar conformations, showing that potential energies in vacuo are not sufficient to understand the nucleosides. Deoxythymidine (but not other pyrimidines) significantly populates the syn orientation. Guanine favors the syn orientation more than adenine. The ribose favors the syn orientation significantly more than the deoxyribose. The NORTH pucker coexists with the syn conformers. A hydrogen bond is frequently formed between the 5'-OH group and the syn bases, despite competition by water. The rate of the anti/syn transitions with purines is on the nanosecond time scale, confirming a long held assumption underpinning the interpretation of ultrasonic relaxation studies. Therefore, our knowledge of the structure and dynamics of nucleosides in solvent is only limited by the accuracy of the potential used to simulate them, and it is shown that such simulations provide a distinct and unique test of nucleic acid force fields. This confirmed that the widely distributed CHARMM27 force field is, overall, well-balanced with a particularly good representation of the ribose. Specific improvements, however, are suggested for the deoxyribose and torsion gamma.     

Theoretical scrutinization of nine benzoic acid dimers: Stability and energy decomposition analysis

Aromatic carboxylic acids are able to form diverse dimers and multimers due to their hydrogen bond donor and acceptor cites, as well as the aromatic rings. In this work, we examine nine benzoic acid dimers stabilized by hydrogen bonding and stacking interactions. Interacting quantum atoms methodology revealed that dominant attractive interactions in all of them, including hydrogen bonded systems, are due to exchange-correlation. Coulomb interactions are significant only in the most stable dimer with a double hydrogen bond, although the corresponding energy term is almost two times lower compared to the nonclassical one. Since interacting quantum atoms approach treats monomers binding by considering electronic energy only, in order to examine dissociation kinetics we performed density functional theory-based molecular dynamics simulations of selected stacked dimers: in 40% of the studied systems at 300 K thermal energy was sufficient to overpower barrier for dissociation within 1 ps, which resulted in the separation of the monomers, whereas 20% of them remained in the stacked position even after 5 ps. These results highlight the importance of noncovalent interactions, particularly weak stacking interactions, on the structure and dynamics of carboxylic acids and their derivatives.     

Ab initio and ABEEM/MM fluctuating charge model studies of dimethyl phosphate anion in a microhydrated environment

Dimethyl phosphate (DMP) anion has been used extensively as a model compound to simulate the properties of phosphate group. A 35-point DMP anion potential model is constructed based on the atom-bond electronegativity equalization fluctuating charge molecular force field (ABEEM/MM), and it is employed to study the properties of gas-phase DMP anion and DMP-(H₂O) _n (n = 1–3) clusters. The ABEEM/MM model reproduces well the properties obtained by available experiments and QM calculations, including charge distributions, geometries, and conformational energies of gas-phase DMP-water complexes. Furthermore, molecular dynamics simulation on the DMP anion in aqueous solution based on the ABEEM/MM shows that a remarkable first hydration shell around the nonesterified oxygen atom of DMP anion is formed with a coordination number of 5.2. It is also found that two hydrogen atoms of one water molecule form two hydrogen bonds with two nonesterified oxygen atoms of DMP anion simultaneously. This work could be used as a starting point for us to establish the ABEEM/MM nucleic acid force field.     

Synthesis of novel di-Se-containing thymidine and Se-DNAs for structure and function studies

The selenium derivatization of nucleic acids and nucleic acid-protein complexes has provided a powerful tool to solve phase problem in X-ray crystallography.Selenium atoms in the nucleotides can serve as fine scattering centers in crystal diffraction.Towards the synthesis of multiple selenium atom-containing nucleotides,which offers strong phasing power to facilitate crystal structure determination,we report here the synthesis of the thymidine analogue containing two Se atoms in one nucleobase.The novel Se-containing nucleoside and oligonucleotide DNAs were synthesized and found with the red-shifted UV spectrum and yellow color.Their unique properties are useful in phase determination,nucleic acid-based detection as well as spectroscopic studies of nucleic acids and nucleic acid-protein complexes.     

Chemical shifts in nucleic acids studied by density functional theory calculations and comparison with experiment

NMR chemical shifts are highly sensitive probes of local molecular conformation and environment and form an important source of structural information. In this study, the relationship between the NMR chemical shifts of nucleic acids and the glycosidic torsion angle, χ, has been investigated for the two commonly occurring sugar conformations. We have calculated by means of DFT the chemical shifts of all atoms in the eight DNA and RNA mono-nucleosides as a function of these two variables. From the DFT calculations, structures and potential energy surfaces were determined by using constrained geometry optimizations at the BP86/TZ2P level of theory. The NMR parameters were subsequently calculated by single-point calculations at the SAOP/TZ2P level of theory. Comparison of the (1) H and (13) C?NMR shifts calculated for the mono-nucleosides with the shifts determined by NMR spectroscopy for nucleic acids demonstrates that the theoretical shifts are valuable for the characterization of nucleic acid conformation. For example, a clear distinction can be made between χ angles in the anti and syn domains. Furthermore, a quantitative determination of the χ angle in the syn domain is possible, in particular when (13) C and (1) H chemical shift data are combined. The approximate linear dependence of the C1' shift on the χ angle in the anti domain provides a good estimate of the angle in this region. It is also possible to derive the sugar conformation from the chemical shift information. The DFT calculations reported herein were performed on mono-nucleosides, but examples are also provided to estimate intramolecularly induced shifts as a result of hydrogen bonding, polarization effects, or ring-current effects.     

Directionally negative friction: a method for enhanced sampling of rare event kinetics

A method exploiting the properties of an artificial (nonphysical) Langevin dynamics with a negative frictional coefficient along a suitable manifold and positive friction in the perpendicular directions is presented for the enhanced calculation of time-correlation functions for rare event problems. Exact time-correlation functions that describe the kinetics of the transitions for the all-positive, physical system can be calculated by reweighting the generated trajectories according to stochastic path integral treatment involving a functional weight based on an Onsager-Machlup action functional. The method is tested on a prototypical multidimensional model system featuring the main elements of conformational space characteristic of complex condensed matter systems. Using the present method, accurate estimates of rate constants require at least three order of magnitudes fewer trajectories than regular Langevin dynamics. The method is particularly useful in calculating kinetic properties in the context of multidimensional energy landscapes that are characteristic of complex systems such as proteins and nucleic acids.     

Calculation of structural behavior of indirect NMR spin-spin couplings in the backbone of nucleic acids

Calculated indirect NMR spin-spin coupling constants (J-couplings) between (31)P, (13)C, and (1)H nuclei were related to the backbone torsion angles of nucleic acids (NAs), and it was shown that J-couplings can facilitate accurate and reliable structural interpretation of NMR measurements and help to discriminate between their distinct conformational classes. A proposed stepwise procedure suggests assignment of the J-couplings to torsion angles from the sugar part to the phosphodiester link. Some J-couplings show multidimensional dependence on torsion angles, the most prominent of which is the effect of the sugar pucker. J-couplings were calculated in 16 distinct nucleic acid conformations, two principal double-helical DNAs, B- and A-, the main RNA form, A-RNA, as well as in 13 other RNA conformations. High-level quantum mechanics calculations used a baseless dinucleoside phosphate as a molecular model, and the effect of solvent was included. The predicted J-couplings correlate reliably with available experimental data from the literature.     

Spectroscopic quantification of covalently immobilized oligonucleotides

Quantitative determination of surface coverage, film thickness and molecular orientation of DNA oligomers covalently attached to aminosilane self‐assembled monolayers has been obtained using complementary infrared and photoelectron studies. Spectral variations between surface immobilized oligomers of the different nucleic acids are reported for the first time. Carbodiimide condensation was used for covalent attachment of phosphorylated oligonucleotides to silanized aluminum substrates. Fourier transform infrared (FTIR) spectroscopy and x‐ray photoelectron spectroscopy (XPS) were used to characterize the surfaces after each modification step. Infrared reflection–absorption spectroscopy of covalently bound DNA provides orientational information. Surface density and layer thickness are extracted from XPS data. The surface density of immobilized DNA, 2–3 (×10¹³) molecules cm^?2, was found to depend on base composition. Comparison of antisymmetric to symmetric phosphate stretching band intensities in reflection–absorption spectra of immobilized DNA and transmission FTIR spectra of DNA in KBr pellet indicates that the sugar–phosphate backbone is predominantly oriented with the sugar–phosphate backbone lying parallel to the surface, in agreement with the 10–20 Å DNA film thickness derived from XPS intensities. Copyright © 2004 John Wiley & Sons, Ltd.     

Metal‐Modified Nucleic Acids: Metal‐Mediated Base Pairs,Triples, and Tetrads

The incorporation of metal ions into nucleic acids by means of metal‐mediated base pairs represents a promising and prominent strategy for the site‐specific decoration of these self‐assembling supramolecules with metal‐based functionality. Over the past 20 years, numerous nucleoside surrogates have been introduced in this respect, broadening the metal scope by providing perfectly tailored metal‐binding sites. More recently, artificial nucleosides derived from natural purine or pyrimidine bases have moved into the focus of Ag^I‐mediated base pairing, due to their expected compatibility with regular Watson–Crick base pairs. This minireview summarizes these advances in metal‐mediated base pairing but also includes further recent progress in the field. Moreover, it addresses other aspects of metal‐modified nucleic acids, highlighting an expansion of the concept to metal‐mediated base triples (in triple helices and three‐way junctions) and metal‐mediated base tetrads (in quadruplexes). For all types of metal‐modified nucleic acids, proposed or accomplished applications are briefly mentioned, too.     

Extended weak bonding interactions in DNA: pi-stacking (base-base), base-backbone, and backbone-backbone interactions

We report on several weak interactions in nucleic acids, which, collectively, can make a nonnegligible contribution to the structure and stability of these molecules. Fragments of DNA were obtained from previously determined accurate experimental geometries and their electron density distributions calculated using density functional theory (DFT). The electron densities were analyzed topologically according to the quantum theory of atoms in molecules (AIM). A web of closed-shell bonding interactions is shown to connect neighboring base pairs in base-pair duplexes and in dinuleotide steps. This bonding underlies the well-known pi-stacking interaction between adjacent nucleic acid bases and is characterized topologically for the first time. Two less widely appreciated modes of weak closed-shell interactions in nucleic acids are also described: (i) interactions between atoms in the bases and atoms belonging to the backbone (base-backbone) and (ii) interactions among atoms within the backbone itself (backbone-backbone). These interactions include hydrogen bonding, dihydrogen bonding, hydrogen-hydrogen bonding, and several other weak closed-shell X-Y interactions (X, Y = O, N, C). While each individual interaction is very weak and typically accompanied by perhaps 0.5-3 kcal/mol, the sum total of these interactions is postulated to play a role in stabilizing the structure of nucleic acids. The Watson-and-Crick hydrogen bonding is also characterized in detail at the experimental geometries as a prelude to the discussion of the modes of interactions listed in the title.