DNA Nucleobases Research Articles

The discovery of isomers of DNA nucleobases produced by ionisation

The discovery of isomers of DNA nucleobases produced by ionisation

Association between oxidized nucleobases and mitochondrial DNA damage with long-term mortality in patients with sepsis

BackgroundSepsis not only leads to short-term mortality during hospitalization, but is also associated with increased mortality during long-term follow-up after hospital discharge. Metabolic stress during sepsis may cause oxidative damage to both nuclear and mitochondrial DNA (mtDNA) and RNA, which could affect long-term health and life span. Therefore, the aim of this study was to assess the association of sepsis with oxidized nucleobases and (mt)DNA damage and long-term all-cause mortality in septic patients. Methods91 patients with sepsis who visited the emergency department (ED) of the University Medical Center Groningen between August 2012 and June 2013 were included. Urine and plasma were collected during the ED visit. Septic patients were matched with 91 healthy controls. Death rate was obtained until June 2020.The degree of oxidation of DNA, RNA and free nucleobases were assessed in urine by mass-spectrometry. Lipid peroxidation was assessed in plasma using a TBAR assay. Additionally, plasma levels of mtDNA and damage to mtDNA were determined by qPCR. ResultsSepsis patients denoted higher levels of oxidated DNA, RNA, free nucleobases and lipid peroxidation than controls (all p < 0.01). Further, sepsis patients displayed an increase in plasma mtDNA with an increase in mtDNA damage compared to matched controls (p < 0.01). Kaplan meier survival analyses revealed that high degrees of RNA- and nucleobase oxidation were associated with higher long-term all-cause mortality after sepsis (p < 0.01 and p = 0.01 respectively). Of these two, high RNA oxidation was associated with long-term all-cause mortality, independent of adjustment for age, medical history and sepsis severity (HR 1.29 [(1.17–1.41, 95% CI] p < 0.01). ConclusionsSepsis is accompanied with oxidation of nuclear and mitochondrial DNA and RNA, where RNA oxidation is an independent predictor of long-term all-cause mortality. In addition, sepsis causes mtDNA damage and an increase in cell free mtDNA in plasma.

Whither Second-Sphere Coordination?

Whither Second-Sphere Coordination?

Quantum Mechanical Study of some Intercalating and Groove Binding Anticancer Drugs with AT and GC Base Pair of DNA Nucleobase

Anticancer drugs bind with DNA nucleobase pairs (AT and GC) through different binding modes such as intercalation, groove binding, covalent binding etc. Quantum mechanical DFT method is quite useful for computing the interaction energy value for anticancer drug-DNA nucleobase complexes. In our study, we have taken some of the anticancer drugs to investigate the interaction energy for drug-DNA complexes. Among the different binding modes of anticancer drugs; minor and major groove binding in DNA base pair is also an important aspect for anticancer drugs; therefore some anticancer drugs may be minor groove specific and some may be major groove specific. Since, such sequence-specific experimental studies for drug-DNA nucleobase complexes are very complicated and hence this may be investigated by using quantum mechanical theoretical studies, using M062X basis set. Our studies reveal that the stacked models of anticancer drugs-DNA nucleobase (AT and GC) complexes always show negative interaction energy values and among all such complexes the most negative interaction energy value results the most stable and favoured stacked systems. The stacking interaction energies for anticancer drugs-DNA nucleobase (AT and GC) complexes can easily be reflected in the interaction of energy plots.

Substituent effect of benzyl moiety in nitroquinoxaline small molecules upon DNA binding: Cumulative destacking of DNA nucleobases leading to histone eviction

Cooperative disruption of Watson-Crick hydrogen bonds, as well as base-destacking, is shown to be triggered by a quinoxaline-based small molecule consisting of an N,N-dimethylaminopropyl tether, and a para-substituted benzyl moiety. This events lead to superstructure formation and DNA condensation as evident from biophysical experiments and classical molecular dynamics simulations. The DNA superstructure formation by mono-quinoxaline derivatives is highly entropically favored and predominantly driven by hydrophobic interactions. Furthermore, oversupercoiling of DNA and base-destacking cumulatively induces histone eviction from in-vitro assembled nucleosomes at lower micromolar concentrations implicating biological relevance. The DNA structural modulation and histone eviction capacity of the benzyl para-substituents are in the order: –I > –CF3> -Br > -Me > -OMe > –OH, which is largely guided by the polarity of benzyl para-substituent and the resulting molecular topology. The most hydrophobic derivative 3c with para-iodo benzyl moiety causes maximal disruption of base pairing and generation of superstructures. Both these events gradually diminish as the polarity of the benzyl para-substituent increases. On the other hand, quinoxaline derivatives having heterocyclic ring instead of benzyl ring, or in the absence of N,N-dimethylamino head-group, is incapable of inducing any DNA structural change and histone eviction. Further, the quinoxaline compounds displayed potent anticancer activities against different cancer cell lines which directly correlates with the hydrophobic effects of the benzyl para-substituents. Overall, the present study provides new insights into the mechanistic approach of DNA structural modulation driven histone eviction guided by the hydrophobicity of synthesized compounds leading to cellular cytotoxicity towards cancer cells.

Mixed ligand copper(II) complexes of diimine co-ligands: Synthesis, characterization, DNA binding and DNA cleavage activity

Four mixed ligand copper(II) complexes having general formula [Cu(acox)(diimine)]2+1–4, (acox is acenaphthylene-1,2-dione dioxime) have been synthesised and characterized by suitable analytical techniques. The diimine ligands used for the isolation of complexes are bipyridine (bpyn 1), phenanthroline (phne, 2), phenanthroline-5,6-dione (5,6-dione, 3) and dipyridoquinoxaline (dpqn, 4). The degree of binding affinity of complexes with DNA has been assessed using UV–Visible absorption spectroscopic technique, which reveals that the complex that possesses dpqn ligand binds with DNA more strongly than its analogue complexes. The planar geometry of dpqn ligand assists the intercalation of complex partially in between the nucleobases of DNA. On the other hand, the higher hydrophobicity of 5,6-dione in 3 is accountable for its higher DNA-binding affinity than that of bpyn and phne complexes. The trend of DNA binding affinity of complexes observed by ethidium bromide displacement assay and viscosity studies attest the results observed in absorption spectral titration of complexes with DNA. All the four Cu(II) complexes cleave supercoiled plasmid DNA in ACN/Tris(HCl)-NaCl buffer in the absence of an activating agent. Also, these complexes display prominent DNA cleavage activity in presence of hydrogen peroxide and the results indicated that the DNA-cleaving ability of complexes varies in the order 4 > 3 > 2 > 1, and the highest ability of 4 in H2O2 to cleave DNA indicates that it could be developed as efficient chemical nuclease.

Indium nitride nanotube interaction with different DNA nucleobases: Quantum chemical analysis

DNA sequencing gives us an ideal opportunity to promote the well-being by helping personal or precision medicine. Here, we inspected the interaction of DNA nucleobases with the InNNT by using DFT computations in order to find a DNA sequencer. We found that the nucleobases prefer to be adsorbed perpendicularly on the InNNT rather than horizontally. The energy released upon the DNA nucleobases adsorption on the InNNT shows the order of guanine (G, 1.62 eV) > thymine (T, 1.49) > cytosine (C, 1.45) > adenine (A, 0.82). Based on our analysis of energy decomposition, the mainly the nature of perpendicular and horizontal interaction is covalent and π-π interaction, respectively. The nucleobase interaction may meaningfully increase the electrical conductivity of the InNNT, so the sensing response of InNNT to G, T, C, and A nucleobases was anticipated to be 289, 100, 91, and 13 respectively. Based on the results, there is a possibility of using InNNT for sensing the difference among G, T, C, and A nucleobases selectively, being helpful to determine the nucleobase sequence in DNA.

DFT analysis of Thymine adsorption on Ti doped graphene for biosensor applications

Density functional theory quantum chemical calculations have been performed to investigate the adsorption of thymine on pristine graphene (Gr) and Titanium doped graphene (GrTi) in order to explore the potential of doped graphene as adsorbent for biomolecule DNA nucleobase thymine. The various parameters including adsorption energy, mode of charge transfer, dipole moment, HOMO-LUMO gap and DOS confirms the Ti doped graphene can be good candidate as adsorbent for thymine in terms of biosensor applications.

Evaluation of the Anticancer and DNA-Binding Characteristics of Dichloro(diimine)zinc(II) Complexes

Several metal diimine complexes have been reported to possess anticancer properties. To evaluate the anticancer properties of tetrahedral zinc(II) diimine complexes, six complexes were synthesized with the general formula M(N^N)Cl2 {where M = Zn, Pt and N^N = 2,2’-biquinoline (1), 2,2’-dipyridylketone (2) and 4-((pyridine-2-ylmethylene)amino)phenol (3)}. In general, the intrinsic DNA-binding constants for the different compounds exhibited values within close proximity; the changes in the viscosity of the CT-DNA upon binding to the compounds suggest intercalation-binding mode. Molecular docking study predicted that complexes containing the highly planar ligand 2,2’-biquinoline are capable to establish π–π interactions with nucleobases of the DNA; the other four complexes engaged in donor–acceptor interactions with DNA nucleobases. The six complexes and two reference drugs (cisplatin and sunitinib) were tested against two cancer cell lines (COLO 205 and RCC-PR) and one normal cell line (LLC-MK2), highlighting the better performance of the zinc(II) complexes compared to their platinum(II) analogues. Moreover, zinc(II) complexes have higher selectivity index values than the reference drugs, with promising anticancer properties.

DNA nucleobase interaction driven electronic and optical fingerprints in gallium selenide monolayer for DNA sequencing devices

The interaction of DNA nucleobases with monolayer GaSe has been studied with in DFT framework using vdW functional. We found that nucleobases are physisorbed on the GaSe monolayer. The order of binding energy per atom is C > T > G > A. The room temperature recovery time estimated to be maximum of 113.88 µs for T + GaSe indicting reusability of the GaSe based devices. The modulation in the electronic structures of GaSe has been clearly captured within the simulated STM measurements. We also demonstrate quantum capacitance as a key parameter for sensing applications. Furthermore, in optical properties, electron energy loss (EEL) spectra show red shift in photon energy on nucleobase adsorption in UV region. The red shift is maximum of 0.92 eV for E⊥c and 0.50 eV for E||c. In nutshell, GaSe monolayer exhibit anisotropic optical response in UV-region which can be highly beneficial for developing polarized optical sensors. Our results demonstrate that GaSe monolayer can be utilized to fabricate reusable DNA sequencing devices for biotechnology and medical science.

Structural Basis for The Recognition of Deaminated Nucleobases by An Archaeal DNA Polymerase.

With increasing temperature, nucleobases in DNA become increasingly damaged by hydrolysis of exocyclic amines. The most prominent damage includes the conversion of cytosine to uracil and adenine to hypoxanthine. These damages are mutagenic and put the integrity of the genome at risk if not repaired appropriately. Several archaea live at elevated temperatures and thus, are exposed to a higher risk of deamination. Earlier studies have shown that DNA polymerases of archaea have the property of sensing deaminated nucleobases in the DNA template and thereby stalling the DNA synthesis during DNA replication providing another layer of DNA damage recognition and repair. However, the structural basis of uracil and hypoxanthine sensing by archaeal B‐family DNA polymerases is sparse. Here we report on three new crystal structures of the archaeal B‐family DNA polymerase from Thermococcus kodakarensis (KOD) DNA polymerase in complex with primer and template strands that have extended single stranded DNA template 5’‐overhangs. These overhangs contain either the canonical nucleobases as well as uracil or hypoxanthine, respectively, and provide unprecedented structural insights into their recognition by archaeal B‐family DNA polymerases.

Study of the physical step interaction of the proton with DNA molecules using analytical approach and Monte-Carlo simulation

Ionization cross-section calculations are analytically presented for proton collisions from DNA nucleobases guanine, adenine, thymine, and cytosine based upon the semi-empirical Rudd model. New parameterizations are used to calculate the excitation and change–charge cross-sections from liquid water. We explored the differential electron cross-sections of biological atom shells to calculate the total stopping cross section for protons with DNA bases. We, therefore, studied the Bragg peak position for protons in a wide range from 100 eV to 20 MeV of impact energy. The obtained results showed a reasonable agreement with available experimental data and calculations from Monte-Carlo (MC) method, GEANT4, and SRIM toolkits.

Study of Electrical and Thermoelectrical Properties of One Strand DNA Chain for Nanoscale Thermoelectric Applications

The concept of using DNA molecules for designing nano-scale electronic systems has attracted researcher’s attention due to the unique properties of DNA, such as self-assembly and self-recognition. Thus, increased number of studies, theoretically and experimentally, have been carried out to study the possibility of adopting DNA molecules in designing nanoscale thermoelectric devices. In this work, a general expression of the electron transmission probability that describes the electron transfer through one strand DNA chain has been derived using the steady-state-formalism by assuming one strand of DNA molecules as line model. The energy-dependent transmission was studied, then energy-and temperature-dependent Seebeck coefficient, and thermoelectric characteristics of four one strand DNA sequences: (A-A)10, (C-C)10, (G-G)10 and (T-T)10 are theoretically studied. According to the obtained results, it is found that the transmission behavior (magnitude and position) is varying with the type of DNA sequence. Also, the energy dependent Seebeck coefficient (S-E) curves clearly show a nonlinear energy-dependence, while the relationship between Seebeck coefficient and temperature (S-T) is linear. Thermoelectric power factor as a function of temperature was found to be enhanced with the temperature increment for the four types of DNA nucleobases. The highest values of thermoelectric power factor belong to thymine (120Wm-1K-2) and cytosine (60 Wm-1K-2), that nominate them as outstanding candidate thermoelectric materials to be adopted in the fabrication of one strand DNA-base nanoscale thermoelectric devices.

Electronic Conductance and Current Modulation through Graphdiyne Nanopores for DNA Sequencing

Solid-state nanopore devices have emerged as one of the most promising technologies that may decode the sequence of DNA nucleobases by reading electronic conductance and electric current signals. Herein we study the potential of atomically thick graphdiyne (GDY) to act as an all-electronic nanopore (NP)-based DNA sequencing device. The first-principles density functional theory method is used to study the structural properties, interaction energy (Ei) values, translocation time (τ), charge transfer [Q(e)] values, charge density difference [Δρ(r)], molecular orbital (MO) positions, and electronic density of states (DOS) properties of the GDYNP and GDYNP + nucleobase (nucleobases: adenine (A), guanine (G), thymine (T), and cytosine (C)) systems. Our results suggest that the GDYNP system could be a suitable device for the detection of nucleobases due to their specific translocation times inside the GDYNP device. The Δρ(r) results reveal that the charge fluctuates around the GDYNP edges close to the target nucleobase. This charge reorganization causes the modulation of charge transport in the GDYNP device. Furthermore, the GDYNP device is used to read-out the conductance and current signals of each DNA nucleobase while located inside the GDYNP by using nonequilibrium Green’s functions formalism. Our findings show a change in conductance with respect to the reference bare “GDYNP” device for energy values below/above the Fermi energy. The conductance as well as current sensitivity (%) values (C > G > T > A) indicates that the nucleobases could possibly be sequenced through the GDYNP device. Further, each nucleobase transmits unique current signals when transported through the GDYNP device. A distinction between purine- and pyrimidine-type nucleobases seems possible due to their different current signals. Thus, our study highlights the potentials that would motivate research toward the development of the GDYNP device, which may be even a better DNA nucleobase detector compared to graphene-based devices.

Customizable and Regioselective One-Pot N−H Functionalization of DNA Nucleobases to Create a Library of Nucleobase Derivatives for Biomedical Applications

Customizable and Regioselective One-Pot N−H Functionalization of DNA Nucleobases to Create a Library of Nucleobase Derivatives for Biomedical Applications

Customizable and Regioselective One‐Pot N−H Functionalization of DNA Nucleobases to Create a Library of Nucleobase Derivatives for Biomedical Applications

AbstractDNA is one of the most exciting biomolecules in nature for developing supramolecular biofunctional nanoarchitectures owing to the highly specific and selective interactions between complementary Watson‐Crick base pairing. Herein, simple and one‐pot synthetic procedures have been implemented for producing a library of DNA nucleobase derivatives endowed with reactive functional groups for bioconjugation and cross‐linking strategies with other (bio)molecules. Purine and pyrimidine molecules have been regioselectively N−H functionalized either via N‐alkylation, N‐allylation, N‐propargylation or Michael‐type reactions and structurally characterized. The influence of the reaction conditions was assessed and discussed. The in vitro biocompatibility of the native and nucleobase derivatives was evaluated by culturing them with human fibroblasts, revealing their cytocompatibility. The library of nucleobase derivatives holds great promise for being coupled to different biomolecules, including biopolymeric materials, lipids, and peptides, thus potentially leading to modular supramolecular nanobiomaterials for biomedicine.

Adsorptive Removal of Heavy Metal Ions, Organic Dyes, and Pharmaceuticals by DNA-Chitosan Hydrogels.

DNA–chitosan (DNA–CS) hydrogel was prepared by in situ complexation between oppositely charged DNA and chitosan polyelectrolytes via electrostatic cross-linking to study its adsorption characteristics. The DNA–chitosan hydrogel matrix contains (i) cationic (NH3+) and anionic (PO4−) sites for electrostatic binding with ionic species, (ii) -OH and -NH2 groups and heteroaromatic DNA nucleobases for chelation of heavy metal ions, and (iii) DNA double-helix for recognition and binding to small organic molecules of various structures and polarities. DNA–CS hydrogels efficiently bind with Hg2+, Pb2+, Cd2+, and Cu2+ metal cations of significant environmental concern. Adsorption capacities of DNA–CS hydrogels for studied metal ions depend on hydrogel composition and pH of solution and reach ca. 50 mg/g at neutral pHs. Hydrogels with higher DNA contents show better adsorption characteristics and notably higher adsorption capacity to Hg2+ ions. Because of the co-existence of cationic and anionic macromolecules in the DNA–CS hydrogel, it demonstrates an affinity to both anionic (Congo Red) and cationic (Methylene Blue) dyes with moderate adsorption capacities of 12.6 mg/g and 29.0 mg/g, respectively. DNA–CS hydrogel can also be used for adsorptive removal of pharmaceuticals on conditions that their molecules are sufficiently hydrophobic and have ionogenic group(s). Facile preparation and multitarget adsorption characteristics of DNA–CS hydrogel coupled with sustainable and environmentally friendly characteristics render this system promising for environmental cleaning applications.

DNA nucleobase sequencing by aluminum nitride nanosheets in gas or water medium

DNA nucleobase sequencing by aluminum nitride nanosheets in gas or water medium

X- and gamma-rays attenuation properties of DNA nucleobases by using FLUKA simulation code

X- and gamma-rays attenuation properties of DNA nucleobases by using FLUKA simulation code

Mechanism-Based Insights into Removing the Mutagenicity of Aromatic Amines by Small Structural Alterations.

Aromatic and heteroaromatic amines (ArNH2) are activated by cytochrome P450 monooxygenases, primarily CYP1A2, into reactive N-arylhydroxylamines that can lead to covalent adducts with DNA nucleobases. Hereby, we give hands-on mechanism-based guidelines to design mutagenicity-free ArNH2. The mechanism of N-hydroxylation of ArNH2 by CYP1A2 is investigated by density functional theory (DFT) calculations. Two putative pathways are considered, the radicaloid route that goes via the classical ferryl-oxo oxidant and an alternative anionic pathway through Fenton-like oxidation by ferriheme-bound H2O2. Results suggest that bioactivation of ArNH2 follows the anionic pathway. We demonstrate that H-bonding and/or geometric fit of ArNH2 to CYP1A2 as well as feasibility of both proton abstraction by the ferriheme-peroxo base and heterolytic cleavage of arylhydroxylamines render molecules mutagenic. Mutagenicity of ArNH2 can be removed by structural alterations that disrupt geometric and/or electrostatic fit to CYP1A2, decrease the acidity of the NH2 group, destabilize arylnitrenium ions, or disrupt their pre-covalent transition states with guanine.