Hg(II) ion specifically binds with T:T mismatched base pair in duplex DNA

Metal-mediated base pair formation, resulting from the interaction between metal ions and artificial bases in oligonucleotides, has been developed for its potential application in nanotechnology. We have recently found that the T:T mismatched base pair binds with Hg(II) ions to generate a novel metal-mediated base pair in duplex DNA. The thermal stability of the duplex with the T-Hg-T base pair was comparable to that of the corresponding T:A or A:T. The novel T-Hg-T base pair involving the natural base thymine is more convenient than the metal-mediated base pairs involving artificial bases due to the lack of time-consuming synthesis. Here, we examine the specificity and thermodynamic properties of the binding between Hg(II) ions and the T:T mismatched base pair. Only the melting temperature of the duplex with T:T and not of the perfectly matched or other mismatched base pairs was found to specifically increase in the presence of Hg(II) ions. Hg(II) specifically bound with the T:T mismatched base pair at a molar ratio of 1:1 with a binding constant of 10(6) M(-1), which is significantly higher than that for nonspecific metal ion-DNA interactions. Furthermore, the higher-order structure of the duplex was not significantly distorted by the Hg(II) ion binding. Our results support the idea that the T-Hg-T base pair could eventually lead to progress in potential applications of metal-mediated base pairs in nanotechnology.     

非共价作用对气相中B-DNA双螺旋结构稳定性的贡献:基于GEBF方法的密度泛函理论计算

采用密度泛函理论, 将基于能量的分子片方法(GEBF)应用于气相中优化B型脱氧核糖核酸(碱基对数目N=2, 5, 10)双螺旋构型的结构. 通过比较M06-2X泛函和其他方法(B3LYP、B3LYP-vdW和TPSS泛函)的结果, 发现不考虑碱基之间的π-π堆积作用将会导致碱基之间的纵向距离拉长. 随着体系双螺旋链长的增加, 没有考虑碱基堆积作用而导致的相邻碱基纵向距离拉长的程度快速衰减. 计算表明, 气相中B-DNA双螺旋结构的稳定性来源于其作用力(主要是氢键和π-π堆积作用)的协同性, 对不多于10组碱基对的体系而言, 其氢键的贡献明显大于碱基堆积作用.     

A theoretical study of structures and electron affinities of radical anions of guanine-cytosine, adenine-thymine, and hypoxanthine-cytosine base pairs

Adiabatic electron affinities (AEA) and structural perturbations due to addition of an excess electron to each of the neutral guanine-cytosine (G-C), adenine-thymine (A-T), and hypoxanthine-cytosine (HX-C) base pairs were studied using the self-consistent charge, density functional tight-binding (SCC-DFTB-D) method, augmented by the empirical London dispersion energy term. Performance of the SCC-DFTB-D method was examined by comparing the calculated results using it with those obtained from experiment as well as ab initio and other different density functional theoretical studies. An excellent agreement between the SCC-DFTB-D results and those obtained by the other calculations regarding the structural modifications, hydrogen bonding, and dissociation energies of the neutral and radical anion base pairs was found. It is shown that adiabatic electron affinity can be better predicted by considering reaction enthalpies of formation of the respective neutral and anionic base pairs from their respective molecular components instead of taking the difference between their total energies. The calculated AEAs of the base pairs were compared with those obtained by the bracketing method from Schaefer and coworkers, where a satisfactory agreement was found. It shows applicability of the SCC-DFTB-D method to study charged DNA models at a highly economical computational cost.     

Understanding hydrogenation of the adenine‐thymine base pairs and their anions: A density functional study

The B3LYP/DZP++ approach has been used to investigate the properties of hydrogenated radicals and anions of adenine‐thymine (A‐T) base pairs. Our calculations show that the hydrogenated radicals and anions have relatively high stabilities compared with the single adenine and thymine base. The conformations and hydrogen‐bond interactions of A‐T base pairs have obviously changed once the hydrogen atoms attached to the A‐T base pairs and their anion. As for the hydrogenated A‐T radicals, all of them exhibit relatively high electron affinities and different hydrogenation properties with respect to their components. The process of the bond formations of (C6)‐H (adenine) and (C6)‐H (thymine) are the most favorable in energetics. The two hydrogenation channels have the reaction Gibbs free energies (ΔG°) of ?51.8 and ?54.2 kcal mol^?1, respectively. Also, the calculations on the basis of CPCM model imply that the solvent effect plays an important role in the electron attachment and hydrogenation reactions, and can stabilize the hydrogenated A‐T anions. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Synthesis and properties of oligonucleotides with iodo-substituted aromatic aglycons: investigation of possible halogen bonding base pairs

Ab initio calculations of halogen bond energies of artificial base pairs constructed between iodinated aromatic nucleobase mimics and nitrogen-containing acceptor molecules such as pyridine and imidazole suggest that modified base pairs are converted to optimized planar base pairs with weak Delta E values of -0.19 to -3.93 kcal/mol. To evaluate the contribution of halogen bonding toward duplex stabilization of such modified nucleobase mimics introduced into artificial base pairs, we synthesized three C-nucleoside analogues 1-3 with several iodinated aromatic rings and an imidazole nucleoside derivative 4 and incorporated them into oligodeoxynucleotides. Hybridization studies of modified oligodeoxynucleotides incorporating iodoaromatic bases showed their unique universal base-like ability; however, no indication of halogen bond formation was observed. A more sophisticated design is required for the development of new base pairs stabilized by halogen bonding.     

Deciphering the role of hydrogen bonding in enhancing pDNA-polycation interactions

There is considerable interest in the binding and condensation of DNA with polycations to form polyplexes because of their possible application to cellular nucleic acid delivery. This work focuses on studying the binding of plasmid DNA (pDNA) with a series of poly(glycoamidoamine)s (PGAAs) that have previously been shown to deliver pDNA in vitro in an efficient and nontoxic manner. Herein, we examine the PGAA-pDNA binding energetics, binding-linked protonation, and electrostatic contribution to the free energy with isothermal titration calorimetry (ITC). The size and charge of the polyplexes at various ITC injection points were then investigated by light scattering and zeta-potential measurements to provide comprehensive insight into the formation of these polyplexes. An analysis of the calorimetric data revealed a three-step process consisting of two different endothermic contributions followed by the condensation/aggregation of polyplexes. The strength of binding and the point of charge neutralization were found to be dependent upon the hydroxyl stereochemistry of the carbohydrate moiety within each polymer repeat unit. Circular dichroism spectra reveal that the PGAAs induce pDNA secondary structure changes upon binding, which suggest a direct interaction between the polymers and the DNA base pairs. Infrared spectroscopy experiments confirmed both base pair and phosphate group interactions and, more specifically, showed that the stronger-binding PGAAs had more pronounced interactions at both sites. Thus, we conclude that the mechanism of poly(glycoamidoamine)-pDNA binding is most likely a combination of electrostatics and hydrogen bonding in which long-range Coulombic forces initiate the attraction and hydroxyl groups in the carbohydrate comonomer, depending on their stereochemistry, further enhance the association through hydrogen bonding to the DNA base pairs.     

Preparation of supramolecular chromophoric assemblies using a DNA duplex

Organization of supramolecular assemblies of chromophores with precisely-controlled orientation and sequence remains challenging. Nucleic acids with complementary base sequences spontaneously form double-helical structures. Therefore, covalent attachment of chromophores to DNA or RNA can be used to control assembly and orientation of chromophores. In this perspective, we first review our recent work on the assemblies of fluorophores (pyrene and perylene) by using natural base pairs. The interaction between dyes can be strictly controlled by means of cluster and interstrand wedge motifs. We then discuss novel artificial base pairs that can suppress the interaction between fluorophores and nucleobases. We incorporated a cyclohexane moiety into DNA, and showed that these artificial base pairs suppressed the electron-hole transfer between fluorophores and nucleobases and enhanced the quantum yields of fluorophores. These base pairs can potentially be used to accumulate fluorophores inside DNA duplexes without decreasing quantum yields.     

Halogen bonding in DNA base pairs

Halogen bonding (R-X···Y) is a qualitative analogue of hydrogen bonding that may prove useful in the rational design of artificial proteins and nucleotides. We explore halogen-bonded DNA base pairs containing modified guanine, cytosine, adenine and thymine nucleosides. The structures and stabilities of the halogenated systems are compared to the normal hydrogen bonded base pairs. In most cases, energetically stable, coplanar structures are identified. In the most favorable cases, halogenated base pair stabilities are within 2 kcal mol(-1) of the hydrogen bonded analogues. Among the halogens X = Cl, Br, and I, bromine is best suited for inclusion in these biological systems because it possesses the best combination of polarizability and steric suitability. We find that the most stable structures result from a single substitution of a hydrogen bond for a halogen bond in dA:dT and dG:dC base pairs, which allows 1 or 2 hydrogen bonds, respectively, to complement the halogen bond.     

Base pairing in RNA structures: A computational analysis of structural aspects and interaction energies

The base pairing patterns in RNA structures are more versatile and completely different as compared to DNA. We present here results of ab-initio studies of structures and interaction energies of eight selected RNA base pairs reported in literature. Interaction energies, including BSSE correction, of hydrogen added crystal geometries of base pairs have been calculated at the HF/6-31G** level. The structures and interaction energies of the base pairs in the crystal geometry are compared with those obtained after optimization of the base pairs. We find that the base pairs become more planar on full optimization. No change in the hydrogen bonding pattern is seen. It is expected that the inclusion of appropriate considerations of many of these aspects of RNA base pairing would significantly improve the accuracy of RNA secondary structure prediction.     

Structural Basis for Expansion of the Genetic Alphabet with an Artificial Nucleobase Pair

Hydrophobic artificial nucleobase pairs without the ability to pair through hydrogen bonds are promising candidates to expand the genetic alphabet. The most successful nucleobase surrogates show little similarity to each other and their natural counterparts. It is thus puzzling how these unnatural molecules are processed by DNA polymerases that have evolved to efficiently work with the natural building blocks. Here, we report structural insight into the insertion of one of the most promising hydrophobic unnatural base pairs, the dDs–dPx pair, into a DNA strand by a DNA polymerase. We solved a crystal structure of KlenTaq DNA polymerase with a modified template/primer duplex bound to the unnatural triphosphate. The ternary complex shows that the artificial pair adopts a planar structure just like a natural nucleobase pair, and identifies features that might hint at the mechanisms accounting for the lower incorporation efficiency observed when processing the unnatural substrates.     

Revisiting the effects of sequence and structure on the hydrogen bonding and π-stacking interactions in nucleic acids

Calculated electron densities from PBE0/6-31+G(d,p) were analyzed with respect to the hydrogen bonding within a nucleic acid base pair and the π-stacking between sets of base pairs. From published X-ray crystallographic data, base pairs were isolated from a total of 11 DNA and RNA duplexes, and their experimental geometry was maintained throughout the analyses. Focusing solely on Watson-Crick base pairs, from the values of the electron density between interacting nuclei (at the bond critical points), we provide quantitative data on individual weak interactions. For hydrogen bonding, in addition to quantifying the scissoring effect in GC base pairs, the origin of the controversy around the relative stability of AT and AU base pairs is identified and resolved. Thus, it is illustrated how the conclusion as to their relative stability rests on the specific choice of oligonucleotides compared. For π-stacking, sequence effects for tandem AT base pairs are captured, quantified, and explained, and the greater sensitivity of GC, over AT, sequences to the rise parameter is established. The results presented here show that, from experimental geometries and their electron densities, previously determined effects of the sequence and structure of a duplex on the stabilizing interactions can be captured, quantified, and traced back to the geometry of the base pairs.     

Parallel DNA Constrained by“CC~ Clamps”

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MP2 study on the hydrogen bonding interaction between 5-hydroxy-5-methylhydantoin and DNA bases: A,C, G,T

The 5-hydroxy-5-methylhydantoin (5-OH-5-Me-dHyd) is a nucleobase lesion induced by the action of ionizing radiation on thymine residue in DNA. In this study, we present the hydrogen bonding base pairs involving 5-OH-5-Me-dHyd bound to the four bases in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T). Full geometry optimizations have been performed for the studied complexes by MP2 method. The interaction energies were corrected for the basis-set superposition error (BSSE), using the full Boys–Bernardi counterpoise correction scheme. Hydrogen bonding patterns of these base pairs were characterized using NBO analysis and AIM analysis. According to the calculated binding energies and structural parameters, the stability of the base pairs decrease in the following order: 5-OH-5-Me-dHyd:G>5-OH-5-Me-dHyd:A>5-OH-5-Me -dHyd:C~5-OH-5-Me-dHyd:T.     

5-Aza-7-deazaguanine–Isoguanine and Guanine–Isoguanine Base Pairs in Watson–Crick DNA: The Impact of Purine Tracts,Clickable Dendritic Side Chains,and Pyrene Adducts

The Watson–Crick coding system depends on the molecular recognition of complementary purine and pyrimidine bases. Now, the construction of hybrid DNAs with Watson–Crick and purine–purine base pairs decorated with dendritic side chains was performed. Oligonucleotides with single and multiple incorporations of 5-aza-7-deaza-2′-deoxyguanosine, its tripropargylamine derivative, and 2′-deoxyisoguanosine were synthesized. Duplex stability decreased if single modified purine–purine base pairs were inserted, but increased if pyrene residues were introduced by click chemistry. A growing number of consecutive 5-aza-7-deazaguanine–isoguanine base pairs led to strong stepwise duplex stabilization, a phenomenon not observed for the guanine–isoguanine base pair. Spacious residues are well accommodated in the large groove of purine–purine DNA tracts. Changes to the global helical structure monitored by circular dichroism spectroscopy show the impact of functionalization to the global double-helix structure. This study explores new areas of molecular recognition realized by purine base pairs that are complementary in hydrogen bonding, but not in size, relative to canonical pairs.     

Effect of Alkali Metal Cations on Length and Strength of Hydrogen Bonds in DNA Base Pairs

For many years, non-covalently bonded complexes of nucleobases have attracted considerable interest. However, there is a lack of information about the nature of hydrogen bonding between nucleobases when the bonding is affected by metal coordination to one of the nucleobases, and how the individual hydrogen bonds and aromaticity of nucleobases respond to the presence of the metal cation. Here we report a DFT computational study of nucleobase pairs interacting with alkali metal cations. The metal cations contribute to the stabilization of the base pairs to varying degrees depending on their position. The energy decomposition analysis revealed that the nature of bonding between nucleobases does not change much upon metal coordination. The effect of the cations on individual hydrogen bonds were described by changes in VDD charges on frontier atoms, H-bond length, bond energy from NBO analysis, and the delocalization index from QTAIM calculations. The aromaticity changes were determined by a HOMA index.     

The Expanded Genetic Alphabet

All biological information, since the last common ancestor of all life on Earth, has been encoded by a genetic alphabet consisting of only four nucleotides that form two base pairs. Long‐standing efforts to develop two synthetic nucleotides that form a third, unnatural base pair (UBP) have recently yielded three promising candidates, one based on alternative hydrogen bonding, and two based on hydrophobic and packing forces. All three of these UBPs are replicated and transcribed with remarkable efficiency and fidelity, and the latter two thus demonstrate that hydrogen bonding is not unique in its ability to underlie the storage and retrieval of genetic information. This Review highlights these recent developments as well as the applications enabled by the UBPs, including the expansion of the evolution process to include new functionality and the creation of semi‐synthetic life that stores increased information.     

Dissecting the Vaporization Enthalpies of Ionic Liquids by Exclusively Experimental Methods: Coulomb Interaction,Hydrogen Bonding,and Dispersion Forces

The quantification of hydrogen bonding and dispersion energies from vaporization enthalpies is a great challenge. Dissecting interaction energies is particularly difficult for ionic liquids (ILs), for which the composition of the different types of interactions is known neither for the liquid nor for the gas phase. In this study, we demonstrate the existence of ion pairs in the gas phase and dissect the interaction energies exclusively from measured vaporization enthalpies of different alkylated protic ILs (PILs) and aprotic ILs (AILs) and the molecular analogues of their cations. We demonstrate that the evaporated ion pairs are characterized by H‐bond‐enhanced Coulomb interaction. The overall interaction energy for the ILs in the bulk phase is composed of Coulomb interaction (76 kJ mol^?1), hydrogen bonding (38 kJ mol^?1), and minor dispersion interaction (10 kJ mol^?1). Thus, hydrogen bonding prominently contributes to the overall interaction energy of PILs, which is reflected in the properties of this class of liquids.     

核酸碱基的非谐性振动:正规及错配碱基对的一维和二维红外光谱及其结构基础

用量子化学计算研究了正规Watson-Crick碱基对和四例典型的错配碱基对.对碱基单体和二聚体进行了详细的非谐性频率分析,以揭示其结构方面的一些振动特征.研究发现这些振动特征能在模拟的一维和二维红外光谱中很好地表现出来.利用势能分布研究了所选简正模式的离域化程度,发现从孤立的碱基单体到参与氢键的二聚体,模式的离域化程度变化很大;同时,这些模式的非谐性常数也发生了相应的改变.以人们通常认为的位于红外光谱中6-μm波长区域的羰基伸缩模式为例进行了探讨.     

High‐Field NMR Spectroscopy Reveals Aromaticity‐Modulated Hydrogen Bonding in Heterocycles

From DNA base pairs to drug–receptor binding, hydrogen (H‐)bonding and aromaticity are common features of heterocycles. Herein, the interplay of these bonding aspects is explored. H‐bond strength modulation due to enhancement or disruption of aromaticity of heterocycles is experimentally revealed by comparing homodimer H‐bond energies of aromatic heterocycles with analogs that have the same H‐bonding moieties but lack cyclic π‐conjugation. NMR studies of dimerization in C₆D₆ find aromaticity‐modulated H‐bonding (AMHB) energy effects of approximately ±30 %, depending on whether they enhance or weaken aromatic delocalization. The attendant ring current perturbations expected from such modulation are confirmed by chemical shift changes in both observed ring C−H and calculated nucleus‐independent sites. In silico modeling confirms that AMHB effects outweigh those of hybridization or dipole–dipole interaction.