Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.129
Filtrar
Mais filtros










Filtros aplicados

Base de dados
Intervalo de ano de publicação
1.
Nat Commun ; 11(1): 781, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034123

RESUMO

Recent evidence demonstrates that novel protein-coding genes can arise de novo from non-genic loci. This evolutionary innovation is thought to be facilitated by the pervasive translation of non-genic transcripts, which exposes a reservoir of variable polypeptides to natural selection. Here, we systematically characterize how these de novo emerging coding sequences impact fitness in budding yeast. Disruption of emerging sequences is generally inconsequential for fitness in the laboratory and in natural populations. Overexpression of emerging sequences, however, is enriched in adaptive fitness effects compared to overexpression of established genes. We find that adaptive emerging sequences tend to encode putative transmembrane domains, and that thymine-rich intergenic regions harbor a widespread potential to produce transmembrane domains. These findings, together with in-depth examination of the de novo emerging YBR196C-A locus, suggest a novel evolutionary model whereby adaptive transmembrane polypeptides emerge de novo from thymine-rich non-genic regions and subsequently accumulate changes molded by natural selection.


Assuntos
Evolução Molecular , Proteínas de Membrana/genética , Proteínas de Saccharomyces cerevisiae/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Timina , Fator de Transcrição TFIID/genética , Adaptação Biológica/genética , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Regulação Fúngica da Expressão Gênica , Aptidão Genética , Membranas Intracelulares/metabolismo , Proteínas de Membrana/química , Fases de Leitura Aberta , Domínios Proteicos/genética , Saccharomyces cerevisiae/genética
2.
PLoS Genet ; 16(2): e1008390, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32084124

RESUMO

Base J, ß-D-glucosyl-hydroxymethyluracil, is a modification of thymine DNA base involved in RNA Polymerase (Pol) II transcription termination in kinetoplastid protozoa. Little is understood regarding how specific thymine residues are targeted for J-modification or the mechanism of J regulated transcription termination. To identify proteins involved in J-synthesis, we expressed a tagged version of the J-glucosyltransferase (JGT) in Leishmania tarentolae, and identified four co-purified proteins by mass spectrometry: protein phosphatase (PP1), a homolog of Wdr82, a potential PP1 regulatory protein (PNUTS) and a protein containing a J-DNA binding domain (named JBP3). Gel shift studies indicate JBP3 is a J-DNA binding protein. Reciprocal tagging, co-IP and sucrose gradient analyses indicate PP1, JGT, JBP3, Wdr82 and PNUTS form a multimeric complex in kinetoplastids, similar to the mammalian PTW/PP1 complex involved in transcription termination via PP1 mediated dephosphorylation of Pol II. Using RNAi and analysis of Pol II termination by RNA-seq and RT-PCR, we demonstrate that ablation of PNUTS, JBP3 and Wdr82 lead to defects in Pol II termination at the 3'-end of polycistronic gene arrays in Trypanosoma brucei. Mutants also contain increased antisense RNA levels upstream of transcription start sites, suggesting an additional role of the complex in regulating termination of bi-directional transcription. In addition, PNUTS loss causes derepression of silent Variant Surface Glycoprotein genes involved in host immune evasion. Our results suggest a novel mechanistic link between base J and Pol II polycistronic transcription termination in kinetoplastids.


Assuntos
DNA de Cinetoplasto/metabolismo , Proteínas de Protozoários/metabolismo , RNA Polimerase II/metabolismo , Terminação da Transcrição Genética , Trypanosoma brucei brucei/fisiologia , Animais , DNA de Cinetoplasto/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genes de Protozoários , Glucosídeos/metabolismo , Glucosiltransferases/genética , Glucosiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Leishmania/fisiologia , Mutação , Proteínas de Protozoários/genética , Interferência de RNA , RNA Polimerase II/genética , Timina/metabolismo , Uracila/análogos & derivados , Uracila/metabolismo
3.
Nucleic Acids Res ; 48(7): 3542-3552, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32064528

RESUMO

MeCP2 is a nuclear protein that binds to sites of cytosine methylation in the genome. While most evidence confirms this epigenetic mark as the primary determinant of DNA binding, MeCP2 is also reported to have an affinity for non-methylated DNA sequences. Here we investigated the molecular basis and in vivo significance of its reported affinity for non-methylated GT-rich sequences. We confirmed this interaction with isolated domains of MeCP2 in vitro and defined a minimal target DNA sequence. Binding depends on pyrimidine 5' methyl groups provided by thymine and requires adjacent guanines and a correctly orientated A/T-rich flanking sequence. Unexpectedly, full-length MeCP2 protein failed to bind GT-rich sequences in vitro. To test for MeCP2 binding to these motifs in vivo, we analysed human neuronal cells using ChIP-seq and ATAC-seq technologies. While both methods robustly detected DNA methylation-dependent binding of MeCP2 to mCG and mCAC, neither showed evidence of MeCP2 binding to GT-rich motifs. The data suggest that GT binding is an in vitro phenomenon without in vivo relevance. Our findings argue that MeCP2 does not read unadorned DNA sequence and therefore support the notion that its primary role is to interpret epigenetic modifications of DNA.


Assuntos
DNA/química , DNA/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Sítios de Ligação , Linhagem Celular , Citosina/metabolismo , Guanina/química , Humanos , Motivos de Nucleotídeos , Ligação Proteica , Timina/química
5.
Phys Chem Chem Phys ; 22(5): 2999-3007, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31957771

RESUMO

Infrared multiple photon dissociation (IRMPD) spectroscopy has been used to probe the structures of the three protonated base-pair mismatches containing 9-ethylguanine (9eG) in the gas phase. Computational chemistry has been used to determine the relative energies and compute the infrared spectra of these complexes. By comparing the IRMPD spectra with the computed spectra, in all cases, it was possible to deduce that what was observed experimentally were the lowest energy computed structures. The protonated complex between 9eG and 1-methylthymine (1mT) is protonated at N7 of 9eG-the most basic site of all three bases in this study-and bound in a Hoogsteen type structure with two hydrogen bonds. The experimental IRMPD spectrum for the protonated complex between 9eG and 9-methyladenine (9mA) is described as arising from a combination of the two lowest energy structures, both which are protonated at N1 of adenine and each containing two hydrogen bonds with 9eG being the acceptor of both. The protonated dimer of 9eG is protonated at N7 with an N7-H+-N7 ionic hydrogen bond. It also contains an interaction between a C-H of protonated guanine and the O6 carbonyl of neutral guanine which is manifested in a slight red shift of that carbonyl stretch. The protonated 9eG/9mA structures have been previously identified by X-ray crystallography in RNA and are contained within the protein database.


Assuntos
Gases/química , Guanina/análogos & derivados , Espectrofotometria Infravermelho , Adenina/análogos & derivados , Adenina/química , Adenina/metabolismo , Pareamento Incorreto de Bases , Cristalografia por Raios X , Guanina/química , Guanina/metabolismo , Ligação de Hidrogênio , Modelos Moleculares , Fótons , Timina/análogos & derivados , Timina/química , Timina/metabolismo
6.
Chemistry ; 26(10): 2164-2168, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-31913530

RESUMO

A C-nucleoside with 6-phenyl-1H-carbazole as the base moiety has been synthesized and incorporated in the middle of an oligonucleotide. Mercuration of this modified residue at positions 1 and 8 gave the first example of an oligonucleotide featuring a monofacial dinuclear organometallic nucleobase. The dimercurated oligonucleotide formed stable duplexes with unmodified oligonucleotides placing either cytosine, guanine, or thymine opposite to the organometallic nucleobase. A highly stabilizing (ΔTm =7.3 °C) HgII -mediated base pair was formed with thymine. According to DFT calculations performed at the PBE0DH level of theory, this base pair is most likely dinuclear, with the two HgII ions coordinated to O2 and O4 of the thymine base.


Assuntos
Carbazóis/química , Compostos Organomercúricos/química , Timina/química , Pareamento de Bases , Sequência de Bases , Carbazóis/metabolismo , Teoria da Densidade Funcional , Conformação Molecular , Oligonucleotídeos/síntese química , Oligonucleotídeos/química , Timina/metabolismo , Temperatura de Transição
7.
J Chem Phys ; 152(3): 035101, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31968979

RESUMO

One-electron oxidation of adenine (A) leads initially to the formation of adenine radical cation (A•+). Subsequent deprotonation of A•+ can provoke deoxyribonucleic acid (DNA) damage, which further causes senescence, cancer formation, and even cell death. However, compared with considerable reports on A•+ reactions in free deoxyadenosine (dA) and duplex DNA, studies in non-B-form DNA that play critical biological roles are rare at present. It is thus of vital importance to explore non-B-form DNA, among which the triplex is an emerging topic. Herein, we investigate the deprotonation behavior of A•+ in the TAT triplex with continuous A bases by time-resolved laser flash photolysis. The rate constants for the one-oxidation of triplex 8.4 × 108 M-1 s-1 and A•+ deprotonation 1.3 × 107 s-1 are obtained. The kinetic isotope effect of A•+ deprotonation in the TAT triplex is 1.8, which is characteristic of a direct release of the proton into the solvent similar to free base dA. It is thus elucidated that the A•+ proton bound with the third strand is most likely to be released into the solvent because of the weaker Hoogsteen H-bonding interaction and the presence of the highly mobile hydration waters within the third strand. Additionally, it is confirmed through Fourier transform infrared spectroscopy that the deprotonation of A•+ results in the dissociation of the third strand and disruption of the secondary structure of the triplex. These results provide valuable kinetic data and in-depth mechanistic insights for understanding the adenine oxidative DNA damage in the triplex.


Assuntos
Adenina/química , DNA/química , Elétrons , Timina/química , Ligação de Hidrogênio , Oxirredução
8.
Biomarkers ; 25(2): 144-148, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31916865

RESUMO

Objective: Few studies have investigated haem oxygenase-1 gene (HMOX1) promoter polymorphism in microvascular angina (MVA).Materials and methods: HMOX1 promoter (GT)n repeats were examined in healthy controls (N = 220) and MVA subjects (N = 181).Results: The distribution of genotype of SS, SL and LL were significantly different in MVA (17%, 51%, 33%) vs. normal controls (35%, 46%, 20%) (p < 0.001, S allele: ≤30 repeats, L allele: >30 repeats). In multivariate analysis, carrier of L allele (odds ratio 2.772, p < 0.001) was a significant predictor for the diagnosis of MVA.Conclusions: Subjects with MVA had longer HMOX1 promoter (GT)n repeats than the healthy controls. Trial registration number: NCT01198730 at https://clinicaltrials.gov.


Assuntos
Guanina , Heme Oxigenase-1/genética , Angina Microvascular/genética , Polimorfismo Genético , Timina , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Angina Microvascular/enzimologia , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
9.
Phys Chem Chem Phys ; 22(2): 838-853, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31840715

RESUMO

The five fundamental units of the genetic code: uracil (U), thymine (T), cytosine (C), adenine (A) and guanine (G) are known for extremely low vapor pressure and low thermal stability at elevated temperatures. Therefore, application of conventional techniques for the determination of sublimation enthalpies and vapor pressures fails to provide accurate results. Recently, a Fast Scanning Calorimetry method (FSC) for vapor pressure determination was developed for investigation of extremely low volatile, as well as for thermally unstable molecular and ionic molecules. This success has encouraged application of the FSC method for determination of vapor pressures and sublimation enthalpies of the five nucleobases, where available literature data are in disarray. The thermodynamic data of the nucleobases available in the literature were collected, evaluated, and combined with our experimental results to reconcile available experimental data. The set of evaluated thermochemical data on the five nucleobases was recommended as the benchmark properties for these thermally labile compounds.


Assuntos
Adenina/química , Calorimetria , Citosina/química , Guanina/química , Termodinâmica , Timina/química , Uracila/química , Pressão , Volatilização
10.
Exp Neurol ; 323: 113062, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513786

RESUMO

The excitatory neurotransmitter glutamate is essential in basal ganglia motor circuits and has long been thought to contribute to cell death and degeneration in Parkinson's disease (PD). While previous research has shown a significant role of NMDA and AMPA receptors in both excitotoxicity and PD, the third class of ionotropic glutamate receptors, kainate receptors, have been less well studied. Given the expression of kainate receptor subunits GluK1-GluK3 in key PD-related brain regions, it has been suggested that GluK1-GluK3 may contribute to excitotoxic cell loss. Therefore the neuroprotective potential of the kainate receptor antagonist UBP310 in animal models of PD was investigated in this study. Stereological quantification revealed administration of UBP310 significantly increased survival of dopaminergic and total neuron populations in the substantia nigra pars compacta in the acute MPTP mouse model of PD. In contrast, UBP310 was unable to rescue MPTP-induced loss of dopamine levels or dopamine transporter expression in the striatum. Furthermore, deletion of GluK1, GluK2 or GluK3 had no effect on MPTP or UBP310-mediated effects across all measures. Interestingly, UBP310 did not attenuate cell loss in the midbrain induced by intrastriatal 6-OHDA toxicity. These results indicate UBP310 provides neuroprotection in the midbrain against MPTP neurotoxicity that is not dependent on specific kainate receptor subunits.


Assuntos
Alanina/análogos & derivados , Neurônios Dopaminérgicos/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Transtornos Parkinsonianos/metabolismo , Timina/análogos & derivados , Alanina/farmacologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/metabolismo , Receptores de Ácido Caínico/metabolismo , Timina/farmacologia
11.
J Enzyme Inhib Med Chem ; 34(1): 1730-1739, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31822127

RESUMO

A series of readily accessible 1-(piperidin-3-yl)thymine amides was designed, synthesised and evaluated as Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors. In line with the modelling results, most inhibitors showed reasonable MtbTMPK inhibitory activity. Compounds 4b and 4i were slightly more potent than the parent compound 3. Moreover, contrary to the latter, amide analogue 4g was active against the avirulent M. tuberculosis H37Ra strain (MIC50=35 µM). This finding opens avenues for future modifications.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Timina/farmacologia , Amidas/síntese química , Amidas/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Núcleosídeo-Fosfato Quinase/metabolismo , Relação Estrutura-Atividade , Timina/síntese química , Timina/química
12.
J Phys Chem A ; 123(51): 10862-10867, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31790228

RESUMO

Sulfur-substituted analogues of thymine are of three types depending on the position of sulfur substitution: 2-thiothymine (2tThy), 4-thothymine (4tThy), and 2,4-dithiothymine (dtThy). These molecules, on photoexcitation, are known to form in their triplet state with near unity yield. Consequently, they are able to photosensitize ground state molecular oxygen to singlet oxygen, a property which makes them potential drugs for photodynamic therapy (PDT). The singlet oxygen yield is directly correlated with the triplet lifetime of the thiothymine, which in turn is governed by its triplet decay dynamics. In this work, the dependence of the triplet decay dynamics on the position of sulfur substitution is investigated by comparatively studying all three thiothymines. The topology of the triplet potential energy surface and decay mechanism of 2tThy is found to be distinctly different from 4tThy and dtThy. The fundamental reason for this is the different electronic natures of the two C═X (X = O, S) moieties in each molecule, one of which is conjugated with a C═C bond, while the other is not. Further, it is shown that the triplet lifetime of 2tThy can be increased by manipulating the energetic ordering of its molecular orbitals with unobtrusive substitutions, thus making it a better candidate for a PDT drug.


Assuntos
Teoria Quântica , Enxofre/química , Timina/química , Estrutura Molecular , Fotoquimioterapia , Timina/análogos & derivados
13.
Mikrochim Acta ; 187(1): 62, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853653

RESUMO

Pomegranate-like multicore WO2/W nanocrystals wrapped with layers of multiporous carbon were fabricated via carbonization of a copper(II)-organic framework host and a tungsten-based polyoxometalates guest, and subsequent etching off the metallic copper. The WO2/W@C core-shell nanospheres were employed to modify an electrode for the analysis of the DNA bases thymine (T) and cytosine (C) by differential pulse voltammetry. The WO2/W@C exhibited strongly increased oxidation signal of T and C. Under optimized conditions, the enhanced peak current represented excellent analytical performance for determination of T and C. This is attributed to the synergic effects of the porous multicore-shell microstructure and the use of tungsten-based materials with their excellent electrocatalytic activity for T and C, with typical peaks voltages near 1.26 V and 1.44 V. The calibration plots for T and C extend from 1 to 4000 µM and from 1 to 3000 µM, respectively, and both detection limits are 0.2 µM. The method was successfully applied to the determination of T and C in spiked blood and urine samples, and the recoveries are form 97.3 to 105.0%. Graphic abstractCore-shell nanospheres of type WO2/W-carbon were prepared for highly sensitive simultaneous voltammetric determination of thymine and cytosine.


Assuntos
Técnicas Biossensoriais , Carbono/química , Citosina/análise , Técnicas Eletroquímicas , Nanosferas/química , Timina/análise , Tamanho da Partícula , Propriedades de Superfície , Compostos de Tungstênio/química
14.
Nat Commun ; 10(1): 5321, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757965

RESUMO

Surface-enhanced Raman spectroscopy (SERS) sensing of DNA bases by plasmonic nanopores could pave a way to novel methods for DNA analyses and new generation single-molecule sequencing platforms. The SERS discrimination of single DNA bases depends critically on the time that a DNA strand resides within the plasmonic hot spot. In fact, DNA molecules flow through the nanopores so rapidly that the SERS signals collected are not sufficient for single-molecule analysis. Here, we report an approach to control the residence time of molecules in the hot spot by an electro-plasmonic trapping effect. By directly adsorbing molecules onto a gold nanoparticle and then trapping the single nanoparticle in a plasmonic nanohole up to several minutes, we demonstrate single-molecule SERS detection of all four DNA bases as well as discrimination of single nucleobases in a single oligonucleotide. Our method can be extended easily to label-free sensing of single-molecule amino acids and proteins.


Assuntos
DNA/análise , Nanopartículas Metálicas , Nanoporos , Pinças Ópticas , Imagem Individual de Molécula/métodos , Análise Espectral Raman/métodos , Adenina/análise , Citosina/análise , DNA/química , Ouro , Guanina/análise , Óptica e Fotônica , Timina/análise
15.
Nat Commun ; 10(1): 4818, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645548

RESUMO

Metal-mediated base pairs expand the repertoire of nucleic acid structures and dynamics. Here we report solution structures and dynamics of duplex DNA containing two all-natural C-HgII-T metallo base pairs separated by six canonical base pairs. NMR experiments reveal a 3:1 ratio of well-resolved structures in dynamic equilibrium. The major species contains two (N3)T-HgII-(N3)C base pairs in a predominantly B-form helix. The minor species contains (N3)T-HgII-(N4)C base pairs and greater A-form characteristics. Ten-fold different 1J coupling constants (15N,199Hg) are observed for (N3)C-HgII (114 Hz) versus (N4)C-HgII (1052 Hz) connectivities, reflecting differences in cytosine ionization and metal-bonding strengths. Dynamic interconversion between the two types of C-HgII-T base pairs are coupled to a global conformational exchange between the helices. These observations inspired the design of a repetitive DNA sequence capable of undergoing a global B-to-A-form helical transition upon adding HgII, demonstrating that C-HgII-T has unique switching potential in DNA-based materials and devices.


Assuntos
DNA Forma A/ultraestrutura , DNA de Forma B/ultraestrutura , Mercúrio/química , Pareamento de Bases , Citosina , DNA/química , DNA/ultraestrutura , DNA Forma A/química , DNA de Forma B/química , Metais , Modelos Moleculares , Conformação de Ácido Nucleico , Espectroscopia de Prótons por Ressonância Magnética , Soluções , Timina
16.
Chem Commun (Camb) ; 55(83): 12571-12574, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577282

RESUMO

We herein demonstrate the UV resistance of glycol nucleic acid (GNA) dinucleotides. This resistance sustains the hypothesis of GNA as a nucleic acid prebiotic ancestor on early Earth, a time of intense solar UV light. Such photorobustness, due to the absence of intrastrand base stacking, could offer an opportunity for nanodevice development requiring challenging UV conditions.


Assuntos
Nucleotídeos/química , Nucleotídeos/efeitos da radiação , Timina/análogos & derivados , Raios Ultravioleta , Conformação de Ácido Nucleico/efeitos da radiação , Timina/química
17.
Nat Commun ; 10(1): 4413, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562325

RESUMO

The synthesis of nucleobases in natural environments, especially in interstellar molecular clouds, is the focus of a long-standing debate regarding prebiotic chemical evolution. Here we report the simultaneous detection of all three pyrimidine (cytosine, uracil and thymine) and three purine nucleobases (adenine, xanthine and hypoxanthine) in interstellar ice analogues composed of simple molecules including H2O, CO, NH3 and CH3OH after exposure to ultraviolet photons followed by thermal processes, that is, in conditions that simulate the chemical processes accompanying star formation from molecular clouds. Photolysis of primitive gas molecules at 10 K might be one of the key steps in the production of nucleobases. The present results strongly suggest that the evolution from molecular clouds to stars and planets provides a suitable environment for nucleobase synthesis in space.


Assuntos
Adenina/química , Citosina/química , Hipoxantina/química , Timina/química , Uracila/química , Xantina/química , Adenina/síntese química , Amônia/química , Monóxido de Carbono/química , Citosina/síntese química , Evolução Química , Meio Ambiente Extraterreno , Hipoxantina/síntese química , Gelo , Metanol/química , Estrutura Molecular , Processos Fotoquímicos/efeitos da radiação , Timina/síntese química , Raios Ultravioleta , Uracila/síntese química , Água/química , Xantina/síntese química
18.
Phys Chem Chem Phys ; 21(36): 20095-20106, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31482894

RESUMO

Rational modification of biomolecules especially DNA base pairs for the theoretical design of molecular magnets has attracted extensive interest. In this work, we report a modification strategy for adenine/thymine-based magnets through introducing a N,N-dioxidized pyrazine ring to either adenine or thymine to form ring-expanded bases (noA/noT) based on their experimentally synthesized derivatives. Further functionalization is conducted by double protonation and pairing with a normal complementary base (nohA-T/nohT-A), respectively. The diversity of protonation sites in noA generates totally six nohA-Ts, together with nohT-A forming seven two-step modified topic base pairs. DFT calculations are performed to characterize the magnetic properties and the diradical character, which indicate three diamagnetic (DM) nohA-Ts and three antiferromagnetic (AFM) nohA-Ts with extremely large magnetic coupling constants J ranging from -1279.7 to -2807.4 cm-1, while a relatively mild AFM nohT-A with a J of -194.6 cm-1. The electron separation effect induced by attraction of positive charges originating from protonation is proposed to explain the diradicalization, which is different from the traditional radical-coupler-radical coupling mode. In addition, atomic natural charges and spin densities, and H-bond and molecular orbital analyses are further discussed for verification and deep understanding of the observed unique phenomena. It should be noted that our designed seven topic base pairs have excellent characters including a good synthetic basis, a large scope of the |J| values, and the AFM-DM magnetic conversion or AFM strength modulation controlled by protonation/deprotonation, prototropic tautomerization, base pairing/dissociation, single proton transfer, and even the applied electric field. All these indicate the promising applications in the field of magnetic information storage or switch control. This work highlights the magnetic modification schemes and possible modulation methods of double positive charge doped DNA base pairs by utilizing their potential spin coupling modes.


Assuntos
Pareamento de Bases , DNA/química , Magnetismo , Pirazinas/química , Timina/química , Prótons
19.
Chemistry ; 25(66): 15164-15172, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31538684

RESUMO

UV irradiation induces DNA lesions particularly at dipyrimidine sites. Using time-resolved UV pump (250 nm) and mid-IR probe spectroscopy the triplet pathway of cyclobutane pyrimidine dimer (CPD) formation within TpC and CpT sequences was studied. The triplet state is initially localized at the thymine base but decays with 30 ns under formation of a biradical state extending over both bases of the dipyrimidine. Subsequently this state either decays back to the electronic ground state on the 100 ns time scale or forms a cyclobutane pyrimidine dimer lesion (CPD). Stationary IR spectroscopy and triplet sensitization via 2'-methoxyacetophenone (2-M) in the UVA range shows that the lesions are formed with an efficiency of approximately 1.5 %. Deamination converts the cytosine moiety of the CPD lesions on the time scale of 10 hours into uracil which gives CPD(UpT) and CPD(TpU) lesions in which the coding potential of the initial cytosine base is vanished.


Assuntos
Citosina/química , DNA/química , Timina/química , Sequência de Bases , Dano ao DNA/efeitos da radiação , Desaminação , Dímeros de Pirimidina/química , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Raios Ultravioleta
20.
Phys Chem Chem Phys ; 21(38): 21305-21316, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31549692

RESUMO

4-Thiopyrimidine (e.g., 4-thiouracil (4-TU) and 4-thiothymine (4-TT)) is a typical kind of thiobase. With the sulfur substitution at the C4 position of the canonical pyrimidine nucleobase, 4-thiopyrimidine displays unique photophysical and photochemical properties such as red-shifted maximum absorption peaks and efficient triplet state populations. One of the properties is the photocrosslinking reaction between 4-thiopyrimidine and pyrimidine base, which plays important roles in photochemotherapy and photolabeling applications. By using density functional theory (M06-2X), we have explored the potential energy profiles of the photocrosslinking reaction between 4-thiopyrimidine (4-TU and 4-TT) and thymine in the S0 and T1 states as well as the interaction between the two states. For both (6-4) and (5-4) photocrosslinking reactions, multiple nonadiabatic pathways via minimum energy crossing points (MECPs) between potential surfaces (PESs) of the T1 and S0 states greatly facilitate the proceeding of photocrosslinking reactions and lead to the relatively stable thietane intermediate in the S0 state. The subsequent H migration in the thietane intermediate takes place solely in the S0 state with surmountable energy barriers in bulk solution, resulting in the formation of the photocrosslinked product. This research provides not only a new mechanistic insight into the photocrosslinking reaction for 4-thiopyrimidines but also a rational explanation for the experiments of UVA irradiated Tp4ST dinucleotide and 4-thiothymidine-containing oligonucleotides, facilitating the deep understanding of the synergistic cytotoxicity of 4-thiopyrimidines and UVA as well as the development of alternative phototherapeutic agents and photolabeling probes.


Assuntos
Reagentes para Ligações Cruzadas/química , Pirimidinas/química , Timina/química , Simulação por Computador , Teoria da Densidade Funcional , Luz , Estrutura Molecular , Processos Fotoquímicos , Termodinâmica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA