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1.
Inorg Chem ; 60(20): 15208-15214, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34597021

RESUMO

The use of lanthanide complexes as powerful auxiliaries for biocrystallography prompted us to systematically analyze the influence of the commercial crystallization kit composition on the efficiency of two lanthanide additives: [Eu(DPA)3]3- and Tb-Xo4. This study reveals that the tris(dipicolinate) complex presents a lower chemical stability and a strong tendency toward false positives, which are detrimental for its use in a high-throughput robotized crystallization platform. In particular, the crystal structures of (Mg(H2O)6)3[Eu(DPA)3]2·7H2O (1), {(Ca(H2O)4)3[Eu(DPA)3]2}n·10nH2O (2), and {Cu(DPA)(H2O)2}n (3), resulting from spontaneous crystallization in the presence of a divalent alkaline-earth cation and transmetalation, are reported. On the other hand, Tb-Xo4 is perfectly soluble in the crystallization media, stable in the presence of alkaline-earth dications, and slowly decomposes (within days) by transmetalation with transition metals. The original structure of [Tb4L4(H2O)4]Cl4·15H2O (4) is also described, where L represents a bis(pinacolato)triazacyclononane ligand. This paper also highlights a potential synergy of interactions between Tb-Xo4 and components of the crystallization mixtures, leading to the formation of complex adducts like {AdkA/Tb-Xo4/Mg2+/glycerol} in the protein binding sites. The observation of such multicomponent adducts illustrated the complexity and versatility of the supramolecular chemistry occurring at the surface of the proteins.

2.
Chemistry ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643968

RESUMO

Several urea-inserted organo-polyoxometalates (POMs) derived from polyoxotungstovanadate [P 2 V 3 W 15 O 61 ] 9- were prepared. The insertion of the carbonyl into the polyoxometallic framework activates the urea toward Hydrogen-bond catalysis. This was shown on the Friedel-Crafts arylation of trans -ß-nitrostyrene. Modelling shows that the most stable form of the organo-POMs features a cis-trans arrangement of the two N-H bonds, but that the likely catalytically active trans-trans form is accessible at room temperature. Finally, it is possible that the oxo substituents next to the vanadium atoms may help the approach of the nucleophile via H-bonding.

3.
Nanoscale ; 13(32): 13795-13808, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34477654

RESUMO

Light-activated functional materials capable of remote control over duplex and G-quadruplex (G4) nucleic acids formation at the cellular level are still very rare. Herein, we report on the photoinduced macrocyclisation of a helicenoid quinoline derivative of binaphthol that selectively provides easy access to an unprecedented class of extended heteroaromatic structures with remarkable photophysical and DNA/RNA binding properties. Thus, while the native bisquinoline precursor shows no DNA binding activity, the new in situ photochemically generated probe features high association constants to DNA and RNA G4s. The latter inhibits DNA synthesis by selectively stabilizing G4 structures associated with oncogenic promoters and telomere repeat units. Finally, the light sensitive compound is capable of in cellulo photoconversion, localizes primarily in the G4-rich sites of cancer cells, competes with a well-known G4 binder and shows a clear nuclear co-localization with the quadruplex specific antibody BG4. This work provides a benchmark for the future design and development of a brand-new generation of light-activated target-selective G4-binders.


Assuntos
Corantes Fluorescentes , Quadruplex G , DNA , Ligantes , Telômero
4.
J Phys Chem B ; 125(30): 8572-8580, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34291941

RESUMO

Singlet-triplet interconversions (intersystem crossing, ISC) in organic molecules are at the basis of many important processes in cutting-edge photonic applications (organic light-emitting devices, photodynamic therapy, etc.). Selection rules for these transitions are mainly governed by the spin-orbit coupling (SOC) phenomenon. Although the SOC relies on complex relativistic phenomena, theoreticians have, with time, developed increasingly sophisticated and efficient approaches to gain access to a satisfactory evaluation of its magnitude. However, recent works have highlighted the remarkable and somehow unexpected efficiency of dimers of small conjugated molecules in terms of ISC quantum yields, whose origin has not been completely investigated. In this work, we bring a coupled experimental and theoretical analysis of the origin of the unusually large ISC efficiency on a series of such dimers that differ by their nature (covalent or supramolecular). We show that considering the dynamical nature of the SOC, and especially its dependence on angular orientations between the dimer subunits sometimes overlooked in the literature, it is necessary to rationalize some counterintuitive experimental observations. This combined experimental and theoretical work paves the way for new molecular engineering rules for SOC control.


Assuntos
Fotoquimioterapia , Dimerização
5.
J Phys Chem Lett ; 12(25): 6014-6019, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34165307

RESUMO

Apurinic/apyrimidinic sites are the most common forms of DNA damage under physiological conditions, yet their structural and dynamical behavior within nucleosome core particles has just begun to be investigated and is dramatically different from that of abasic sites in B-DNA. Clusters of two or more abasic sites are repaired even less efficiently and hence constitute hot spots of high mutagenicity notably due to enhanced double-strand break formation. On the basis of an X-ray structure of a 146 bp DNA wrapped onto a histone core, we investigate the structural behavior of two bistranded abasic sites positioned at mutational hot spots during microsecond-range molecular dynamics simulations. Our simulations allow us to probe interactions of histone tails at clustered abasic site locations, with a definitive assignment of the key residues involved in the NCP-catalyzed formation of DNA-protein cross-linking in line with recent experimental findings, and pave the way for a systematic assessment of the response of histone tails to DNA lesions.


Assuntos
Histonas/química , Nucleossomos/metabolismo , Histonas/genética , Histonas/metabolismo , Modelos Moleculares , Mutagênese , Mutação , Nucleossomos/genética , Conformação Proteica
6.
Phys Chem Chem Phys ; 23(19): 11224-11232, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34010374

RESUMO

In the realm of biomolecules, peptides can present a large diversity of structures. Our study sheds new light on the structural interplay between a tris-dipicolinate lanthanide probe and a decapeptide SASYKTLPRG. Although a rather trivial, electrostatically driven interaction was expected, the combination of paramagnetic NMR and molecular dynamics simulations reveals a highly dynamic association process and allows for providing extensive insights into the interaction sites and their occupancy. This study highlights the importance of a large conformational sampling to reconcile characteristic time in NMR with molecular dynamics simulations, where sampling in the microsecond range is needed. This study opens the door for a detailed mechanistic elucidation of the early steps of lanthanide complex-peptide or lanthanide complex-protein interaction or self-assembly processes.


Assuntos
Complexos de Coordenação/química , Elementos da Série dos Lantanídeos/química , Ácidos Picolínicos/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Dinâmica Molecular , Eletricidade Estática
7.
J Chem Phys ; 154(13): 135103, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33832258

RESUMO

Sequence dependence of the (6-4) photoproduct conformational landscape when embedded in six 25-bp duplexes is evaluated along extensive unbiased and enhanced (replica exchange with solute tempering, REST2) molecular dynamics simulations. The structural reorganization as the central pyrimidines become covalently tethered is traced back in terms of non-covalent interactions, DNA bending, and extrusion of adenines of the opposite strands. The close sequence pattern impacts the conformational landscape around the lesion, inducing different upstream and downstream flexibilities. Moreover, REST2 simulations allow us to probe structures possibly important for damaged DNA recognition.


Assuntos
DNA/química , Pirimidinas/química , Pirimidinonas/química , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Processos Fotoquímicos
8.
Inorg Chem ; 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33620206

RESUMO

A metal-induced self-assembly strategy is used to promote the π-dimerization of viologen-based radicals at room temperature and in standard concentration ranges. Discrete box-shaped 2:2 (M:L) macrocycles or coordination polymers are formed in solution by self-assembly of a viologen-based ditopic ligand with cis-[Pd(en)(NO3)2], trans-[Pd(CH3CN)2(Cl)2], or [Pd(CH3CN)4(BF4)2]. Changing the redox state of the bipyridium units involved in the tectons, from their dicationic state to their radical cation state, results in a reversible "inflation/deflation" of the discrete 2:2 (M:L) macrocyclic assemblies associated to a large modification in the size of their inner cavity. Viologen-centered electron transfer is also used to trigger a dissociation of the coordination polymers formed with tetrakis(acetonitrile)Pd(II), the driving force of the disassembling process being the formation of discrete box-shaped 2:2 (M:L) assemblies stabilized by π-dimerization of both viologen cation radicals.

9.
Chemistry ; 27(11): 3670-3674, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33369892

RESUMO

Polyazanes (i.e., higher nuclearity homologues of hydrazines) with increasing numbers of bound nitrogen atoms (from 3 to 5), including the first pentazane ever described, were prepared by the addition of lower-order polyazanes to diazo reagents. A structure was obtained. It was shown that the polynitrogen chains adopt a helical conformation. DFT modeling shows that the arrangement persists in solution. Although the polyazanes are all reducing agents, they become less so as the number of nitrogens increases.

10.
J Phys Chem B ; 124(50): 11371-11378, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33270456

RESUMO

Functionalized supramolecular cages are of growing importance in biology and biochemistry. They have recently been proposed as efficient auxiliaries to obtain high-resolution cocrystallized proteins. Here, we propose a molecular dynamics investigation of the supramolecular association of sulfonated calix-[8]-arenes to cytochrome c starting from initially distant proteins and ligands. We characterize two main binding sites for the sulfonated calixarene on the cytochrome c surface which are in perfect agreement with the previous experiments with regard to the structure (comparison with the X-ray structure PDB 6GD8) and the binding free energies [comparison between the molecular mechanics Poisson-Boltzmann surface area analysis and the isothermal titration calorimetry measurements]. The per-residue decomposition of the interaction energies reveals the detailed picture of this electrostatically driven association and notably the role of arginine R13 as a bridging residue between the two main anchoring sites. In addition, the analysis of the residue behavior by means of a supervised machine learning protocol unveils the formation of a hydrogen bond network far from the binding sites, increasing the rigidity of the protein. This study paves the way toward an automated procedure to predict the supramolecular protein-cage association, with the possibility of a computational screening of new promising derivatives for controlled protein assembly and protein surface recognition processes.


Assuntos
Calixarenos , Simulação de Dinâmica Molecular , Sítios de Ligação , Citocromos c , Ligação Proteica , Proteínas , Termodinâmica
11.
Sci Rep ; 10(1): 17314, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057206

RESUMO

Apurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway. The impact of losing a nucleobase on the conformation and dynamics of B-DNA is well characterized. Yet AP sites seem to present an entirely different chemistry in nucleosomal DNA, with lifetimes reduced up to 100-fold, and the much increased formation of covalent DNA-protein cross-links leading to strand breaks, refractory to repair. We report microsecond range, all-atom molecular dynamics simulations that capture the conformational dynamics of AP sites and their tetrahydrofuran analogs at two symmetrical positions within a nucleosome core particle, starting from a recent crystal structure. Different behaviours between the deoxyribo-based and tetrahydrofuran-type abasic sites are evidenced. The two solvent-exposed lesion sites present contrasted extrahelicities, revealing the crucial role of the position of a defect around the histone core. Our all-atom simulations also identify and quantify the frequency of several spontaneous, non-covalent interactions between AP and positively-charged residues from the histones H2A and H2B tails that prefigure DNA-protein cross-links. Such an in silico mapping of DNA-protein cross-links gives important insights for further experimental studies involving mutagenesis and truncation of histone tails to unravel mechanisms of DPCs formation.


Assuntos
DNA , Simulação de Dinâmica Molecular , Nucleossomos , Animais , Dano ao DNA , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Histonas , Humanos , Conformação de Ácido Nucleico
12.
J Chem Theory Comput ; 16(9): 5972-5981, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810397

RESUMO

The pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion constituting a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with histones affects the lesion mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA-containing 64-PP within the nucleosome core particle by atomic-resolution molecular dynamics simulations and multiscale data analysis. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, the local DNA flexibility at the damaged site is enhanced due to imperfect structural adaptation to restraints imposed by the histone core. If 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent is deformed and exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.


Assuntos
DNA/química , Histonas/química , Simulação de Dinâmica Molecular , Dímeros de Pirimidina/química , Ligação de Hidrogênio , Conformação de Ácido Nucleico , Raios Ultravioleta
13.
J Phys Chem Lett ; 11(7): 2717-2723, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32146808

RESUMO

Functionalized gold nanoparticles are investigated by density functional theory calculations in the context of cancer radiotherapy. Several typical experimental shapes, including nanostars, nanospheres, and nanorods, are modeled by optimizing Au clusters covered by organic monolayers composed of hydrated short-chain polyethylene glycol (PEG) ligands. The PEGylation stabilizes significantly the stellation of decahedral Au54 by deforming significantly its geometry at the spikes. The higher stability of the PEG molecules adsorbed on this stellated nanocluster with respect to the more spherical icosahedral Au55 and truncated octahedral Au79 leads to a larger energy cost to desorb them and thus a weaker propensity for the starred nanoparticle to exchange ligands with the cell membrane, in agreement with experiments. These results open interesting possibilities for advancing our understanding of the cellular uptake of gold nanoparticles.


Assuntos
Nanopartículas Metálicas/química , Polietilenoglicóis/química , Adsorção , Teoria da Densidade Funcional , Ouro/química , Ligantes , Modelos Químicos , Nanosferas/química , Nanotubos/química
14.
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
15.
ACS Nano ; 13(9): 10343-10350, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31490058

RESUMO

Protein crystals with their precise, periodic array of functional building blocks have potential applications in biomaterials, sensing, and catalysis. This paper describes how a highly porous crystalline framework of a cationic redox protein and an anionic macrocycle can be modulated by a small cationic effector. Ternary composites of protein (∼13 kDa), calix[8]arene (∼1.5 kDa), and effector (∼0.2 kDa) formed distinct crystalline architectures, dependent on the effector concentration and the crystallization technique. A combination of X-ray crystallography and density functional theory (DFT) calculations was used to decipher the framework variations, which appear to be dependent on a calixarene conformation change mediated by the effector. This "switch" calixarene was observed in three states, each of which is associated with a different interaction network. Two structures obtained by co-crystallization with the effector contained an additional protein "pillar", resulting in framework duplication and decreased porosity. These results suggest how protein assembly can be engineered by supramolecular host-guest interactions.


Assuntos
Proteínas/química , Calixarenos/química , Cristalização , Citocromos c/metabolismo , Saccharomyces cerevisiae/metabolismo , Soluções
16.
Angew Chem Int Ed Engl ; 58(42): 14940-14943, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31393659

RESUMO

A halogen-bond templated 1:1 macrocyclization in solution is reported. Tetra(iodoperfluorophenyl) ethers were used as halogen-bonded exotemplates in a substoichiometric amount (5 mol %). Pyridine-containing macrocyclic architectures were formed by ruthenium-catalyzed tandem metathesis/transfer hydrogenation sequence using sodium borohydride and methanol as non-dihydrogen hydrogen source. The halogen-bonded stabilization energies were analyzed relying on density functional theory.

17.
Chem Sci ; 10(1): 277-283, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30746081

RESUMO

By using a combination of readily accessible experimental and computational experiments in water, we explored the factors governing the association between polyanionic dyn[4]arene and a series of α,ω-alkyldiammonium ions of increasing chain length. We found that the lock-and-key concept based on the best match between the apolar and polar regions of the molecular partners failed to explain the observed selectivities. Instead, the dissection of the energetic and structural contributions demonstrated that the binding events were actually guided by two crucial solvent-related phenomena as the chain length of the guest increases: the expected decrease of the enthalpic cost of guest desolvation and the unexpected increase of the favourable enthalpy of complex solvation. By bringing to light the decisive enthalpic impact of complex solvation during the binding of polyelectrolytes by inclusion, this study may provide a missing piece to a puzzle that one day could display the global picture of molecular recognition in water.

18.
J Phys Chem Lett ; 10(5): 1092-1098, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30707843

RESUMO

Solvated gold nanoparticles have been modeled in the fluxional regime by density functional theory including dispersion forces for an extensive set of conventional morphologies. The study of isolated adsorption of one water molecule shows that the most stable adsorption forms are similar (corners and edges) regardless of the nanoparticle shape and size, although the adsorption strength differs significantly (0.15 eV). When a complete and explicit water solvation shell interacts with gold nanoclusters, metastable in vacuum and presenting a predominance of (100) square facets (ino-decahedra Au55 and Au147), these nanoparticles are found unstable and transform into the closest morphologies exhibiting mainly (111) triangular facets and symmetries. The corresponding adsorption strength per water molecule becomes independent of shape and size and is enhanced by the formation of two hydrogen bonds on average. For applications in radiotherapy, this study suggests that the shapes of small gold nanoparticles should be homogenized by interacting with the biological environment.

19.
Chemistry ; 25(6): 1573-1580, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30428127

RESUMO

A dynamic supramolecular approach is developed to promote the π-dimerization of viologen radicals at room temperature and in standard concentration ranges. The approach involves cis- or trans-protected palladium centers serving as inorganic hinges linking two functionalized viologens endowed with metal-ion coordinating properties. Based on detailed spectroscopic, electrochemical and computational data, we show that the one-electron electrochemical reduction of the viologen units in different dynamic metal/ligand mixtures leads to the formation of the same intramolecular π-dimer, regardless of the initial environment around the metallic precursor and of the relative ratio between metal and ligand initially introduced in solution. The large-scale electron-triggered reorganization of the building blocks introduced in solution thus involves drastic changes in the stoichiometry and stereochemistry of the palladium/viologen complexes proceeding in some cases through a palladium centered trans→cis isomerization of the coordinated ligands.

20.
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.

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