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1.
Phys Chem Chem Phys ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32057038

RESUMO

Cyclocurcumin is a turmeric component that has attracted much less attention compared to the well-known curcumin. In spite of the less deep characterization of its properties, cyclocurcumin has shown promising anticancer effects when used in combination with curcumin. Especially, due to its peculiar molecular structure, cyclocurcumin can be regarded as an almost ideal photoswitch, whose capabilities can also be exploited for relevant biological applications. Here, by means of state-of-the-art computational methods for electronic excited-state calculations (TD-DFT, MS-CASPT2, and XMS-CASPT2), we analyze in detail the absorption and photoisomerization pathways leading from the more stable trans isomer to the cis one. The different molecular surroundings, taken into account by means of the electrostatic solvent effect and compared with available experimental data, have been found to be critical in describing the fate of irradiated cyclocurcumin: when in non-polar environments, an excited state barrier prevents photoisomerization and favours fluorescence, whereas in polar solvents, an almost barrierless path results in a striking decrease of fluorescence, opening the way toward a crossing region with the ground state and thus funneling the photoproduction of the cis isomer.

2.
J Phys Chem A ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31999922

RESUMO

We have modeled possible photo-oxidative degradation pathways for a set of boron-containing oligothiophenes, which have potential use in organic electronic devices. Photogenerated reactive oxygen species such as hydroxyl radical, hydroperoxyl radical, and singlet and triplet molecular oxygen are taken into account in three main pathways, namely, sulfoxide formation, sequential addition, and stepwise singlet molecular oxygen addition. Density functional theory at the B3LYP level is used to assess the reaction kinetics and thermodynamics. Our findings show that the influence of the number of thiophene rings and the presence of boron is in most cases minor in terms of degradation. The formation of sulfoxide on the thiophene ring is among the easiest degradation pathways if hydroxyl radical is present in the system. The hydroxyl radical attack on the Cß of thiophene ring of BMBE-1T (2,5-bis(E-dimesitylborylethenyl)thiophene) forms the BMBE-1T(C)OH radical adduct which is kinetically and thermodynamically more favorable than the hydroperoxyl radical attack. The stepwise triplet molecular oxygen addition on the BMBE-1T(C)OH radical adduct has a free energy barrier around 19 kcal·mol-1, and it results in thermodynamically stable degradation product via ring cleavage. Stepwise reactions with singlet molecular oxygen have energy barriers of roughly 40 kcal·mol-1. Singlet molecular oxygen attack on the α-carbon of the thiophene ring is kinetically much more favored than the attack on the beta carbon. Our results elucidate the preferred degradation mechanism of the thiophene backbone of the selected photoactive oligomers. Moreover, the findings of this theoretical study clarify the photostability, and hence the potential drawbacks, of the large-scale use of this class of polythiophenes.

3.
J Phys Chem Lett ; 10(22): 7200-7207, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31693374

RESUMO

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.


Assuntos
Proteínas de Bactérias/química , Borrelia burgdorferi/química , Empacotamento do DNA , DNA Bacteriano/química , Histonas/química , Simulação de Dinâmica Molecular , Modelos Moleculares
4.
J Phys Chem Lett ; 10(22): 7133-7140, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31652065

RESUMO

In humans, vision is limited to a small fraction of the whole electromagnetic spectrum. One possible strategy for enhancing vision in deep-red or poor-light conditions consists of recruiting chlorophyll derivatives in the rod photoreceptor cells of the eye, as suggested in the case of some deep-sea fish. Here, we employ all-atom molecular simulations and high-level quantum chemistry calculations to rationalize how chlorin e6 (Ce6), widely used in photodynamic therapy although accompanied by enhanced visual sensitivity, mediates vision in the dark, shining light on a fascinating but largely unknown molecular mechanism. First, we identify persistent interaction sites between Ce6 and the extracellular loops of rhodopsin, the transmembrane photoreceptor protein responsible for the first steps in vision. Triggered by Ce6 deep-red light absorption, the retinal within rhodopsin can be isomerized thus starting the visual phototransduction cascade. Our data largely exclude previously hypothesized energy-transfer mechanisms while clearly lending credence to a retinal isomerization indirectly triggered by singlet oxygen, proposing an alternative mechanism to rationalize photosensitizer-mediated night vision.

5.
Antioxidants (Basel) ; 8(10)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658666

RESUMO

The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences-representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences-have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE-DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes.

6.
J Phys Chem Lett ; 10(21): 6750-6754, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609626

RESUMO

Photodynamic therapy is a promising approach to treat a variety of superficial tumors and other diseases. One of its major limitations arises from its dependence on molecular oxygen, which decreases the efficiency of the therapy in hypoxia conditions commonly developed by solid tumors. The present contribution reveals the molecular mechanism of a modified thymine bearing a nitroimidazole substituent, a photosensitizer able to produce highly harmful interstrand cross-links in the DNA double strand after irradiation selectively in absence of oxygen. The mechanism is resolved at a fully atomistic and electronic level relying on quantum mechanics (CASPT2, coupled-cluster, DFT, and TD-DFT methods), classical molecular dynamics, and advanced biased QM/MM simulations, revealing an energy penalty of ∼8 kcal/mol for the anionic nitromidazole release. Our findings indicate that the global interstrand cross-link production is driven by a combination of multiple factors, namely, the reverse energy penalty, the diffusion of the nitroimidazole anion, and the further reactivity of the formed thymine radical. On the basis of these results, we also suggest some possible strategies to improve the efficiency of interstrand cross-link production.


Assuntos
DNA/química , Nitroimidazóis/química , DNA/metabolismo , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Fármacos Fotossensibilizantes/química , Teoria Quântica
7.
Phys Chem Chem Phys ; 21(42): 23418-23424, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31624816

RESUMO

DNA-protein cross-links constitute bulky DNA lesions that interfere with the cellular machinery. Amongst these stable covalently tethered adducts, the efficient nucleophilic addition of the free amino group of lysines onto the guanine radical cation has been evidenced. In vitro addition of a trilysine peptide onto a guanine radical cation generated in a TGT oligonucleotide is so efficient that competitive addition of a water molecule, giving rise to 8-oxo-7,8-dihydroguanine, is not observed. This suggests a spatial proximity between guanine and lysine for the stabilization of the prereactive complex. We report all-atom microsecond scale molecular dynamics simulations that probe the structure and interactions of the trilysine peptide (KKK) with two oligonucleotides. Our simulations reveal a strong, electrostatically driven yet dynamic interaction, spanning several association modes. Furthermore, the presence of neighbouring cytosines has been identified as a factor favoring KKK binding. Relying on ab initio molecular dynamics on a model system constituted of guanine and methylammonium, we also corroborate a mechanistic pathway involving fast deprotonation of the guanine radical cation followed by hydrogen transfer from ammonium leaving as a result a nitrogen reactive species that can subsequently cross-link with guanine. Our study sheds new light on a ubiquitous mechanism for DNA-protein cross-links also stressing out possible sequence dependences.


Assuntos
Simulação de Dinâmica Molecular , Oligonucleotídeos/química , Oligopeptídeos/química , Sítios de Ligação , Guanina/química , Lisina/química , Teoria Quântica , Termodinâmica
8.
Bioorg Med Chem ; 27(18): 4101-4109, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31371219

RESUMO

The design of conjugates displaying simultaneously high selectivity and high affinity for different subtypes of integrins is a current challenge. The arginine-glycine-aspartic acid amino acid sequence (RGD) is one of the most efficient short peptides targeting these receptors. We report herein the development of linear and cyclic fluoro-C-glycoside"RGD" conjugates, taking advantage of the robustness and hydrophilicity of C-glycosides. As attested by in vitro evaluation, the design of these C-glyco"RGD" with a flexible three-carbon triazolyl linker allows distinct profiles towards αIIbß3 and αvß3 integrins. Molecular-dynamics simulations confirm the suitability of cyclic C-glyco-c(RGDfC) to target αvß3 integrin. These C-glyco"RGD" could become promising biological tools in particular for Positron Emission Tomography imaging.

9.
Chemistry ; 25(68): 15525-15534, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31373410

RESUMO

Thymine radiation-induced fragmentation is characterised by ring opening and the loss of HNCO/NCO. These pathways have been investigated using DFT calculations in the presence of zero, one and two water molecules. In addition to the already characterised stepwise fragmentation mechanism, we propose a novel concerted pathway reported here for the first time. We show that both the stepwise and concerted mechanisms are competitive with activation energies of 2.05 eV and 2.00 eV, respectively, in the gas phase. The effect of microhydration on these mechanisms are examined based on the most stable conformations found by an exploration of the potential energy surface performed by using DFT-based ab initio molecular dynamics. Microhydration is also accompanied by an increase in the activation energies, with respect to gas phase, amounting to 0.47 eV-an increase that is associated to a stabilising effect of water in agreement with recent experimental studies. However, we also point out that this effect is greatly dependent on the specific water arrangement around thymine and could be limited to only 0.13 eV for some configurations.

10.
Antioxidants (Basel) ; 8(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443537

RESUMO

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.

11.
J Phys Chem B ; 123(34): 7365-7371, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365827

RESUMO

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.

12.
J Phys Chem B ; 123(26): 5514-5523, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31192599

RESUMO

We report on the electronic absorption spectra, conformational behavior, and intra- and intermolecular hydrogen bonds of 2,3-(dibenzimidazol-2-yl)-quinoxaline (DBIQ). The experimentally found strong solvent dependence of the absorption spectra of DBIQ solutions cannot be assigned to electronic excitations of the equilibrium ground-state DBIQ structure. Extended consideration including the nonequilibrium structures within the framework of ab initio molecular dynamics (MD) revealed the importance of torsion molecular motions not covered by the static case. The strong impact of solute-solvent hydrogen bonding on stabilization of these nonequilibrium structures and on conformational composition of DBIQ was demonstrated. A presence of twisted nonplanar geometries along the whole MD trajectory was shown to drastically influence not only energies but also characters of electronic excitations, resulting in a change of local π-π* character in a solution of 1,2-dichloroethane to charge-transfer character in polar dimethylsulfoxide.

13.
Dalton Trans ; 48(29): 10915-10926, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31149683

RESUMO

Ligand field enhancing N-heterocyclic carbene (NHC) ligands were recently shown to prevent photo-induced spin crossover in Fe(ii) complexes due to their intricate effects on the electronic excited state structure. Due to their pico- to nanosecond lifetimes, these complexes are now good candidates for photo-sensitizing applications. Herein we report the synthesis and photophysical characterization of a new family of homoleptic Fe(ii) complexes with C^N^C ligands involving diazines as the central N-heteroaromatic ligand. For these four carbene bond complexes, ultrafast transient absorption spectroscopy revealed a significant improvement of the excited-state lifetime. A record 32 ps lifetime was measured for a complex bearing a ligand combining a π-deficient pyrazine nucleus and a benzimidazolylidene as NHC. When compared to other azine-based ligands investigated, we argue that the lifetimes are modulated by a small excited state barrier expressing the ability of the ligand to reach the Fe-N distance needed for internal conversion to the ground state.

14.
DNA Repair (Amst) ; 78: 45-59, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959406

RESUMO

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.


Assuntos
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
15.
Inorg Chem ; 58(8): 5069-5081, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30950264

RESUMO

The control of photophysical properties of iron complexes and especially of their excited states decay is a great challenge in the search for sustainable alternatives to noble metals in photochemical applications. Herein we report the synthesis and investigations of the photophysics of mer and fac iron complexes bearing bidentate pyridyl-NHC ligands, coordinating the iron with three ligand-field-enhancing carbene bonds. Ultrafast transient absorption spectroscopy reveals two distinct excited state populations for both mer and fac forms, ascribed to the populations of the T1 and the T2 states, respectively, which decay to the ground state via parallel pathways. We find 3-4 ps and 15-20 ps excited-state lifetimes, with respective amplitudes depending on the isomer. The longer lifetime exceeds the one reported for iron complexes with tridentate ligands analogues involving four iron-carbene bonds. By combining experimental and computational results, a mechanism based on the differential trapping of the triplet states in spin-crossover regions is proposed for the first time to explain the impact of the fac/ mer isomerism on the overall excited-state lifetimes. Our results clearly highlight the impact of bidentate pyridyl-NHC ligands on the photophysics of iron complexes, especially the paramount role of fac/ mer isomerism in modulating the overall decay process, which can be potentially exploited in the design of new Fe(II)-based photoactive compounds.

16.
Phys Chem Chem Phys ; 21(9): 4810-4821, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30773577

RESUMO

We study at the DFT level the ionization and the fragmentation of uracil in the presence of zero, one and two water molecules, to unravel the effect of microhydration on the reactivity of this nucleobase. We show that the microhydration lowers the adiabatic and vertical ionization potentials by 0.41 eV and 0.22 eV, respectively. Furthermore, microhydration increases the activation energies of the different dissociation channels up to 0.5 eV and restricts the formation of some fragments, in particular those corresponding to the C5-C6 fragmentation pathway. For the first time, our theoretical study shows new transition states and minima not found for the gas phase, hence indicating a change in the fragmentation mechanisms, as well as a stabilizing effect of microhydration, confirming previous experimental studies.

17.
Chemistry ; 25(10): 2519-2526, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30379366

RESUMO

A computational investigation of the triplet excited states of a rhenium complex electronically coupled with a tryptophan side chain and bound to an azurin protein is presented. In particular, by using high-level molecular modeling, evidence is provided for how the electronic properties of the excited-state manifolds strongly depend on coupling with the environment. Indeed, only upon explicitly taking into account the protein environment can two stable triplet states of metal-to-ligand charge transfer or charge-separated nature be recovered. In addition, it is also demonstrated how the rhenium complex plus tryptophan system in an aqueous environment experiences too much flexibility, which prevents the two chromophores from being electronically coupled. This occurrence disables the formation of a charge-separated state. The successful strategy requires a multiscale approach of combining molecular dynamics and quantum chemistry. In this context, the strategy used to parameterize the force fields for the electronic triplet states of the metal complex is also presented.


Assuntos
Azurina/química , Complexos de Coordenação/metabolismo , Pseudomonas aeruginosa/química , Rênio/química , Água/química , Complexos de Coordenação/química , Ligantes , Modelos Moleculares
18.
Front Chem ; 6: 495, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386775

RESUMO

The adequate exploration of the phase space of a chromophore is a fundamental necessity for the simulation of their optical and photophysical properties, taking into account the effects of vibrational motion and, most importantly, the coupling with a (non-homogeneous) molecular environment. A representative set of conformational snapshots around the Franck-Condon region is also required to perform non-adiabatic molecular dynamics, for instance in the framework of surface hopping. Indeed, in the latter case one needs to prepare a set of initial conditions providing a meaningful and complete statistical base for the subsequent trajectory propagation. In this contribution, we propose two new protocols for molecular dynamics-based phase space sampling, called "local temperature adjustment" and "individual QM/MM-based relaxation." These protocols are intended for situations in which the popular Wigner distribution sampling procedure is not applicable-as it is the case when anharmonic or nonlinear vibrations are present-and where regular molecular dynamics sampling might suffer from an inaccurate distribution of internal energy or from inaccurate force fields. The new protocols are applied to the case of phase space sampling of [Re(CO)3(Im)(Phen)]+ (im, imidazole; phen, phenanthroline) in aqueous solution, showing the advantages and limitations of regular Wigner and molecular dynamics sampling as well as the strengths of the new protocols.

19.
Chem Sci ; 9(41): 7902-7911, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30450180

RESUMO

The intrinsic photostability of nucleic acids is intimately related to evolution of life, while its understanding at the molecular and electronic levels remains a challenge for modern science. Among the different decay pathways proposed in the last two decades, the excited-state hydrogen transfer between guanine-cytosine base pairs has been identified as an efficient non-reactive channel to dissipate the excess of energy provided by light absorption. The present work studies the dynamics of such phenomena taking place in a (dG)·(dC) B-DNA homopolymer in water solution using state-of-the-art molecular modelling and simulation methods. A dynamic effect that boosts the photostability of the inter-strand hydrogen atom transfers, inherent to the Watson-Crick base pairing, is unveiled and ascribed to the energy released during the proton transfer step. Our results also reveal a novel mechanism of DNA decay named four proton transfer (FPT), in which two protons of two adjacent G-C base pairs are transferred to form a biradical zwitterionic intermediate. Decay of the latter intermediate to the ground state triggers the transfer of the protons back to the guanine molecules recovering the Watson-Crick structure of the tetramer. This FPT process is activated by the close interaction of a nearby Na+ counterion with the oxygen atoms of the guanine nucleobases and hence represents a photostable channel operative in natural nucleic acids.

20.
Phys Chem Chem Phys ; 20(40): 25666-25675, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30298156

RESUMO

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.


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