核酸碱基互变异构体的结构、稳定性及其物理化学性质

核酸碱基是DNA及RNA分子的重要组成部分, 在基因遗传信息的传递方面起着主导作用. 核酸碱基存在多种互变异构体, 它们在DNA及RNA分子中主要以最稳定的异构体形式存在, 但是在气相或凝聚相中也有少量的其他异构体形式存在. 核酸碱基的稀有互变异构体往往能够引起碱基对的错配对, 这可能会导致DNA及RNA分子形成不规则的结构, 并进一步导致DNA或RNA双螺旋的自发突变. 因此, 对核酸碱基的互变异构体进行系统的研究, 有助于人们深入认识DNA和RNA分子的结构和性质. 国际上有很多研究小组已经通过实验和理论对核酸碱基互变异构体的结构、相对能量及其性质进行了研究. 本文对文献中有关核酸碱基互变异构体的实验和理论研究进行了综述. 在对前人研究进行归纳总结的基础上, 我们利用密度泛函计算对核酸碱基的互变异构体进行了排序, 得到的最优异构体结构参数和相对能量与实验值相比较为一致. 此外, 因为核酸碱基的物理化学性质可以为生物、化学、材料等方面的研究提供重要的基础性信息, 因此我们还对它们的电子亲和能、电离能、质子亲和能等研究进行了总结.     

Electron attachment to DNA and RNA nucleobases: An EOMCC investigation

We report a benchmark theoretical investigation of both vertical and adiabatic electron affinities of DNA and RNA nucleobases: adenine, guanine, cytosine, thymine, and uracil using equation of motion coupled cluster method. The vertical electron affinity (VEA) values of the first five states of the DNA and RNA nucleobases are computed. It is observed that the first electron attached state is energetically accessible in gas phase. Furthermore, an analysis of the natural orbitals exhibits that the first electron attached states of uracil and thymine are valence‐bound in nature and undergo significant structural changes on attachment of an extra electron, which reflects in the deviation of the adiabatic electron affinity (AEA) than that of the vertical ones. Conversely, the first electron attached states of cytosine, adenine, and guanine are in the category of dipole‐bound anions. Their structure, by and large, remain unaffected on attachment of an extra electron, which is evident from the observed small difference between the AEA and VEA values. VEA and AEA values of all the DNA and RNA nucleobases are found to be negative, which implies that the first electron attached states are not stable rather quasi bound. The results of all previous theoretical calculations are out of track and shows large deviation with respect to the experimentally measured values, whereas, our results are found to be in good agreement. Therefore, our computed values can be used as a reliable standard to calibrate new theoretical methods. © 2015 Wiley Periodicals, Inc.     

Thermochemical properties of some vinyl chloride-induced DNA lesions: detailed view from NBO & AIM analysis

Etheno-damaged DNA adducts such as 3,N ⁴-ethenocytosine, N ²,3-ethenoguanine, and 1,N ²-ethenoguanine are associated with carcinogenesis and cell death. These inevitable damages are counteracted by glycosylase enzymes, which cleave damaged nucleobases from DNA. Escherichia coli alkyl purine DNA glycosylase is the enzyme responsible for excising damaged etheno adducts from DNA in humans. In an effort to understand the intrinsic properties of these molecules, we examined gas-phase acidity values and proton affinities (PA) of multiple sites of these molecules as well as equilibrium tautomerization and base pairing properties by quantum mechanical calculations. We also used calculations to compare the acidic and basic properties of these etheno adduct with those of the normal bases—cytosine and guanine nucleobases. We hypothesize that alkyl DNA glycosylase may cleave certain damaged nucleobases as anions and that the active site may take advantage of a nonpolar environment to favor deprotonated cytosine or guanine as a leaving group versus damaged nucleobases.     

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.     

Front Cover: Can Cyanuric Acid and 2,4,6-Triaminopyrimidine Containing Ribonucleosides be Components of Prebiotic RNA? Insights from QM Calculations and MD Simulations (ChemPhysChem 11/2019)

As a step toward assessing their fitness as pre-RNA nucleobases, we employ DFT and MD simulations to analyze the noncovalent interactions of cyanuric acid (CA) and 2,4,6-triaminopyrimidine (TAP), and the structural properties of the associated ribonucleosides (rNs) and oligonucleotides. Our calculations reveal that the TAP : CA pair has a comparable hydrogen-bond strength to the canonical A : U pair. This strengthens the candidature of CA and TAP as prebiotic nucleobases. Further, the stacking between two canonical nucleobases is stronger than those between TAP or CA and a canonical base, as well as those between two TAP and/or CA, which indicates that enhanced stacking may have served as a driving force for the evolution from prebiotic to canonical nucleobases. Similarities in the DFT-derived anti/syn rotational barriers and MD-derived (anti) glycosidic conformation of the CA and TAP rNs and canonical rNs further substantiate their candidature as pre-RNA components. Greater deglycosylation barriers (as obtained by DFT calculations) for TAP rNs compared to canonical rNs suggest TAP rNs indicate higher resistance to environmental factors, while lower barriers indicate that CA rNs were likely more suitable for less-challenging locations. Finally, the tight packing in narrow CA:TAP-containing helices suggests that the prebiotic polymers were shielded from water, which would aid their evolution into self-replicating systems. Our calculations thus support proposals that CA and TAP can act as nucleobases of pre-RNA.     

第一性原理方法预测水相核酸碱基及其代谢物的氧化还原电动势

氧化还原电动势是了解核酸中电荷/电子转移过程以及设计具有新型氧化还原活性的碱基类化合物的重要参数. 本文对82个芳香化合物的氧化还原电动势进行理论预测, 通过计算值和实验值的比较发现: 气相采用B3LYP/6-311++G(2df,2p)//B3LYP/6-31+G(d)方法, 液相采用HF-COSMORS/UAHF方法, 对运用HF- CPCM/UAHF方法在水相重新优化的构型计算溶剂化能, 能有效预测芳香化合物水相氧化还原电动势, 该理论方法计算的绝对均方根误差(RMSD)为0.124 V. 运用该理论方法成功预测了属于芳香化合物的核酸碱基及其代谢物的水相氧化还原电动势. 根据预测结果, 讨论了核酸中电荷/电子转移过程以及结构改变对设计具有新型氧化还原活性的核酸碱基类化合物的影响. 本文为设计具有氧化还原活性的新型核酸碱基类化合物提供了一种理论方法.     

Anhydrous crystals of DNA bases are wide gap semiconductors

We present the structural, electronic, and optical properties of anhydrous crystals of DNA nucleobases (guanine, adenine, cytosine, and thymine) found after DFT (Density Functional Theory) calculations within the local density approximation, as well as experimental measurements of optical absorption for powders of these crystals. Guanine and cytosine (adenine and thymine) anhydrous crystals are predicted from the DFT simulations to be direct (indirect) band gap semiconductors, with values 2.68 eV and 3.30 eV (2.83 eV and 3.22 eV), respectively, while the experimentally estimated band gaps we have measured are 3.83 eV and 3.84 eV (3.89 eV and 4.07 eV), in the same order. The electronic effective masses we have obtained at band extremes show that, at low temperatures, these crystals behave like wide gap semiconductors for electrons moving along the nucleobases stacking direction, while the hole transport are somewhat limited. Lastly, the calculated electronic dielectric functions of DNA nucleobases crystals in the parallel and perpendicular directions to the stacking planes exhibit a high degree of anisotropy (except cytosine), in agreement with published experimental results.     

Nucleobase modification as redox DNA labelling for electrochemical detection

Basic aspects of DNA electrochemistry with a strong focus on the use of modified nucleobases as redox probes for electrochemical bioanalysis are reviewed. Intrinsic electrochemical properties of nucleobases in combination with artificial redox-active nucleobase modifications are frequently applied in this field. Synthetic approaches (both chemical and enzymatic) to base-modified nucleic acids are briefly summarized and their applications in redox labelling are discussed. Finally, analytical applications including DNA hybridization, primer extension, PCR, SNP typing, DNA damage and DNA-protein interaction analysis are presented (critical review, 91 references).     

A study of redox properties of hydralazine hydrochloride,an antihypertensive drug

Hydralazine hydrochloride itself is a reducing agent and its redox properties like other reducing agents vary as the oxidizing agent and applied conditions vary. The redox properties of hydralazine were studied by spectrophotometric method. Formal redox potential of hydralazine was calculated and effect of pH was observed on redox properties of hydralazine.     

Calculating standard reduction potentials of [4Fe–4S] proteins

The oxidation–reduction potentials of electron transfer proteins determine the driving forces for their electron transfer reactions. Although the type of redox site determines the intrinsic energy required to add or remove an electron, the electrostatic interaction energy between the redox site and its surrounding environment can greatly shift the redox potentials. Here, a method for calculating the reduction potential versus the standard hydrogen electrode, E°, of a metalloprotein using a combination of density functional theory and continuum electrostatics is presented. This work focuses on the methodology for the continuum electrostatics calculations, including various factors that may affect the accuracy. The calculations are demonstrated using crystal structures of six homologous HiPIPs, which give E° that are in excellent agreement with experimental results. © 2012 Wiley Periodicals, Inc.     

Nonempirically Tuned Range-Separated DFT Accurately Predicts Both Fundamental and Excitation Gaps in DNA and RNA Nucleobases

Using a nonempirically tuned range-separated DFT approach, we study both the quasiparticle properties (HOMO-LUMO fundamental gaps) and excitation energies of DNA and RNA nucleobases (adenine, thymine, cytosine, guanine, and uracil). Our calculations demonstrate that a physically motivated, first-principles tuned DFT approach accurately reproduces results from both experimental benchmarks and more computationally intensive techniques such as many-body GW theory. Furthermore, in the same set of nucleobases, we show that the nonempirical range-separated procedure also leads to significantly improved results for excitation energies compared to conventional DFT methods. The present results emphasize the importance of a nonempirically tuned range-separation approach for accurately predicting both fundamental and excitation gaps in DNA and RNA nucleobases.     

Photoelectron spectroscopic studies of 5-halouracil anions

The parent negative ions of 5-chlorouracil, UCl(-) and 5-fluorouracil, UF(-) have been studied using anion photoelectron spectroscopy in order to investigate the electrophilic properties of their corresponding neutral halouracils. The vertical detachment energies (VDE) of these anions and the adiabatic electron affinities (EA) of their neutral molecular counterparts are reported. These results are in good agreement with the results of previously published theoretical calculations. The VDE values for both UCl(-) and UF(-) and the EA values for their neutral molecular counterparts are much greater than the corresponding values for both anionic and neutral forms of canonical uracil and thymine. These results are consistent with the observation that DNA is more sensitive to radiation damage when thymine is replaced by halouracil. While we also attempted to prepare the parent anion of 5-bromouracil, UBr(-), we did not observe it, the mass spectrum exhibiting only Br(-) fragments, i.e., 5-bromouracil apparently underwent dissociative electron attachment. This observation is consistent with a previous assessment, suggesting that 5-bromouracil is the best radio-sensitizer among these three halo-nucleobases.     

Absolute rates of hole transfer in DNA

Absolute rates of hole transfer between guanine nucleobases separated by one or two A:T base pairs in stilbenedicarboxamide-linked DNA hairpins were obtained by improved kinetic analysis of experimental data. The charge-transfer rates in four different DNA sequences were calculated using a density-functional-based tight-binding model and a semiclassical superexchange model. Site energies and charge-transfer integrals were calculated directly as the diagonal and off-diagonal matrix elements of the Kohn-Sham Hamiltonian, respectively, for all possible combinations of nucleobases. Taking into account the Coulomb interaction between the negative charge on the stilbenedicarboxamide linker and the hole on the DNA strand as well as effects of base pair twisting, the relative order of the experimental rates for hole transfer in different hairpins could be reproduced by tight-binding calculations. To reproduce quantitatively the absolute values of the measured rate constants, the effect of the reorganization energy was taken into account within the semiclassical superexchange model for charge transfer. The experimental rates could be reproduced with reorganization energies near 1 eV. The quantum chemical data obtained were used to discuss charge carrier mobility and hole-transport equilibria in DNA.     

Possible DNA damage by oxidation products of guanine: A density functional and electron propagator theoretical study

The stability and reactivity of seven guanine oxidation products (GOP), which contain 8‐oxo‐7,8‐dihydroguanine (8‐oxoG) have been studied and compared with the four nucleobases, such as adenine, cytosine, guanine, and thymine. It has been possible with the use of density functional theory and electron propagator theory (EPT), to evaluate their relation with certain ionization induced process, which produce damage to DNA. Using the application of Koopmans's theorem, EPT provides alternatively a reliable way to calculate the vertical ionization potential (VIP) and vertical electron affinity (VEA). This process has been used to obtain other reactivity indexes, such as: electronegativity and hardness. In the nucleobases and the GOP studies, we observed the following: guanine and 8‐oxo‐7,8‐dihydroguanine were the lowest VIP, and 8‐oxoG was the lowest hardness. This let us confirm that these species are the most susceptible to change their electron densities and transform in other GOP. Particularly, the GOP, Sp(R), Sp(S), and Z were the highest VIP. It allows us to say that they are the most stable. Z and Iz were the highest VEA; this suggests that they have a big capacity to accept electrons and form anionic centers in DNA. The GOP, which was considered in this study, showed hardness values between 9.1 and 10.4 because of π‐conjugation; therefore, these GOP could be good candidates to participate in DNA transversions. © 2012 Wiley Periodicals, Inc.     

A prebiotic role for 8-oxoguanosine as a flavin mimic in pyrimidine dimer photorepair

Redox-active enzyme cofactors derived from ribonucleotides have been called "fossils of the RNA world," suggesting that early catalysts employed modified nucleobases to facilitate redox chemistry in primitive metabolism. Here, we show that the common oxidative damage product 8-oxo-7,8-dihydroguanine (OG), when incorporated into a DNA or RNA strand in proximity to a cyclobutane pyrimidine dimer, can mimic the function of a flavin in photorepair. The OG nucleotide acts catalytically in a mechanism consistent with that of photolyase in which the photoexcited state of the purine donates an electron to a pyrimidine dimer to initiate bond cleavage; subsequent back electron transfer regenerates OG. This unusual example of one form of DNA damage, oxidation, functioning to repair another, photodimerization, may provide insight into the origins of prebiotic redox processes.     

The impact of the nucleoside oxidation on the susceptibility to chemical carcinogens studied by first principle and semiempirical quantum chemistry methods

The B3LYP/aug-cc-pvdz and AM1-CI quantum chemistry calculations were used for estimation of adiabatic and vertical ionization potential values of 22 hydroxyl radical modified purine and pyrimidine model nucleosides. Most of studied derivatives are characterized by higher values of IP compared to canonical guanosine, which is known to be the main target for oxidizing agents and chemical carcinogens in cellular DNA. However, three derivatives, namely fapy-guanosine, 8-oxoguanosine and 2-oxoadenosine are characterized by lower IP values than canonical guanosine. Thus, 6,8-diketo- and 6-enol-8-keto-tautomer of 8-oxoguanosine, 6-enol- and 6-keto tautomers of fapy-guanosine as well as 2-keto form of 2-oxoadenosine may be potential hot spot centers for chemical carcinogens. The IEFPCM calculations confirm above conclusion even in the polar environment.     

Effects on the aromatic character of DNA/RNA nucleobases due to its adsorption onto graphene

In the last years, experimental/theoretical studies have shown that graphene has a strong affinity toward nucleobases, serving as a promising nanomaterial for self‐assembly, sensing, and/or sequencing of DNA/RNA constituents. Then, a complete picture of the properties of the nucleobase–graphene systems is required for its use in technological applications. This work describes a detailed quantum chemical analysis of the aromaticity of adsorbed nucleobases on graphene, comparing between aromaticity indexes based on magnetic, geometry, electron density, and electron delocalization properties of graphene–nucleobase systems. Contrary to the stated by magnetic‐based aromaticity criteria (such as nucleus‐independent chemical shifts), it is proved that the aromatic character of nucleobases is not increased/decreased upon binding on graphene. Therefore, magnetic aromaticity criteria are not recommended to analyze aromaticity in related systems, unless a fragmented scheme be adopted. Finally, these results are expected to expand the knowledge about the understanding of biomolecules‐graphene interactions.     

A computational proposal for the experimentally observed discriminatory behavior of hypoxanthine, a weak universal nucleobase

A computational model composed of six nucleobases was used to investigate why hypoxanthine does not yield duplexes of equal stability when paired opposite each of the natural DNA nucleobases. The magnitudes of all nearest-neighbor interactions in a DNA helix were calculated, including hydrogen-bonding, intra- and interstrand stacking interactions, as well as 1-3 intrastrand stacking interactions. Although the stacking interactions in DNA relevant arrangements are significant and account for at least one third of the total stabilization energy in our nucleobase complexes, the trends in the magnitude of the stacking interactions cannot explain the relative experimental melting temperatures previously reported in the literature. Furthermore, although the total hydrogen-bonding interactions explain why hypoxanthine preferentially pairs with cytosine, the experimental trend for the remaining nucleobases (A, T, G) is not explained. In fact, the calculated pairing preference of hypoxanthine matches that determined experimentally only when the sum of all types of nearest-neighbor interactions is considered. This finding highlights a strong correlation between the relative magnitude of the total nucleobase-nucleobase interactions and measured melting temperatures for DNA strands containing hypoxanthine despite the potential role of other factors (including hydration, temperature, sugar-phosphate backbone). By considering a large range of sequence combinations, we reveal that the binding preference of hypoxanthine is strongly dependent on the nucleobase sequence, which may explain the varied ability of hypoxanthine to universally bind to the natural bases. As a result, we propose that future work should closely examine the interplay between the dominant nucleobase-nucleobase interactions and the overall strand stability to fully understand how sequence context affects the universal binding properties of modified bases and to aid the design of new molecules with ambiguous pairing properties.