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J Phys Chem Lett ; 10(22): 7200-7207, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31693374


DNA compaction is essential to ensure the packaging of the genetic material in living cells and also plays a key role in the epigenetic regulation of gene expression. In both humans and bacteria, DNA packaging is achieved by specific well-conserved proteins. Here, by means of all-atom molecular dynamics simulations, including the determination of relevant free-energy profiles, we rationalize the molecular bases for this remarkable process in bacteria, illustrating the crucial role played by positively charged amino acids of a small histone-like protein. We also present compelling evidence that this histone-like protein alone can induce strong bending of a DNA duplex around its core domain, a process that requires overcoming a major free-energy barrier.

Proteínas de Bactérias/química , Borrelia burgdorferi/química , Empacotamento do DNA , DNA Bacteriano/química , Histonas/química , Simulação de Dinâmica Molecular , Modelos Moleculares
Antioxidants (Basel) ; 8(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443537


By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.

J Phys Chem B ; 123(34): 7365-7371, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365827


The behavior of the structural parameters of DNA considering different levels of methylation in CpG islands is studied by means of full-atom molecular dynamics simulations and electronic circular dichroism, both in an artificial model system and in a gene promoter sequence. It is demonstrated that methylation although intrinsically brings quite local perturbations may, if its level is high enough, induce cooperative effects that strongly modify the DNA backbone torsional parameters altering the helicity as compared to the nonmethylated case. Because methylation of the CpG island is correlated with the regulation of gene expression, understanding the structural modifications induced in DNA is crucial to characterize all the fine equilibria into play in epigenetics phenomena.

DNA Repair (Amst) ; 78: 45-59, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959406


Endonuclease III (EndoIII) is a bifunctional DNA glycosylase that removes oxidized pyrimidines from DNA. The genome of Deinococcus radiodurans encodes for an unusually high number of DNA glycosylases, including three EndoIII enzymes (drEndoIII1-3). Here, we compare the properties of these enzymes to those of their well-studied homologues from E. coli and human. Our biochemical and mutational data, reinforced by MD simulations of EndoIII-DNA complexes, reveal that drEndoIII2 exhibits a broad substrate specificity and a catalytic efficiency surpassing that of its counterparts. In contrast, drEndoIII1 has much weaker and uncoupled DNA glycosylase and AP-lyase activities, a characteristic feature of eukaryotic DNA glycosylases, and was found to present a relatively robust activity on single-stranded DNA substrates. To our knowledge, this is the first report of such an activity for an EndoIII. In the case of drEndoIII3, no catalytic activity could be detected, but its ability to specifically recognize lesion-containing DNA using a largely rearranged substrate binding pocket suggests that it may play an alternative role in genome maintenance. Overall, these findings reveal that D. radiodurans possesses a unique set of DNA repair enzymes, including three non-redundant EndoIII variants with distinct properties and complementary activities, which together contribute to genome maintenance in this bacterium.

Reparo do DNA , DNA Complementar/genética , Deinococcus/enzimologia , Deinococcus/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Desoxirribonuclease (Dímero de Pirimidina)/metabolismo , Mutação , Biocatálise , DNA Complementar/metabolismo , Desoxirribonuclease (Dímero de Pirimidina)/química , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica , Pirimidinas/metabolismo , Especificidade por Substrato
Phys Chem Chem Phys ; 20(40): 25666-25675, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30298156


Nucleic acids are constantly exposed to external agents that can induce chemical and photochemical damage. In spite of the great advances achieved in the last years, some molecular mechanisms of DNA damage are not completely understood yet. A recent experimental report (I. Aparici-Espert et al., ACS Chem. Biol. 2018, 13, 542) proved the ability of 5-formyluracil (ForU), a common oxidatively generated product of thymine, to act as an intrinsic sensitizer of nucleic acids, causing single strand breaks and cyclobutane pyrimidine dimers in plasmid DNA. In the present contribution, we use theoretical methodologies to study the triplet photosensitization mechanism of thymine exerted by ForU in a model dimer and in DNA environment. The photochemical pathways in the former system are described combining the CASPT2 and TD-DFT methods, whereas molecular dynamics simulations and QM/MM calculations are employed for the DNA duplex. It is unambiguously shown that the 1n,π* state localised in ForU mediates the population of the triplet manifold, most likely the 3π,π* state centred in ForU, whereas the 3π,π* state localized in thymine can be populated via triplet-triplet energy transfer given the small energy barrier of <0.23 eV determined for this pathway.

DNA/química , Timina/química , Dano ao DNA , Oxirredução , Transtornos de Fotossensibilidade , Dímeros de Pirimidina/metabolismo