Spin Energy Contributions of the Kinetic Energy Density in the Stabilization of the Metal-Ligand Interactions.

The kinetic energy (KE) density plays an essential role in the stabilization mechanism of covalent, polar covalent, and ionic bondings; however, its role in metal-ligand bindings remains unclear. In a recent work, the energetic contributions of the spin densities α and ß were studied to explain the geometrical characteristics of a series of metal-ligand complexes. Notably, the KE density was found to modulate/stabilize the spin components of the intra-atomic nucleus-electron interactions within the metal in the complex. Here, we investigate the topographic properties of the spin components of the KE density for a family of high-spin hexa-aquo complexes ([M(H2O)6]2+) to shed light on the stabilization of the metal-ligand interaction. We compute the Lagrangian, G(r), and Hamiltonian, K(r), KE densities and analyze the evolution of its spin components in the formation of two metal-ligand coordination complexes. We study Kα/ß(r) along the metal-oxygen (M-O) internuclear axis as a function of the metal. Our results indicate that K(r) is a more distance-sensitive quantity compared to G(r) as it displays topographic features at larger M-O distances. Furthermore, K(r) allows one to identify the predominant interaction mechanism in the complexes.

The dopant (n- and p-type)-, band gap-, size- and stress-dependent field electron emission of silicon nanowires.

This study investigates the electron field emission (EFE) of vertical silicon nanowires (Si NWs) fabricated on n-type Si (100) and p-type Si (100) substrates using catalyst-induced etching (CIE). The impact of dopant types (n- and p-types), optical energy gap, crystallite size and stress on EFE parameters has been explored in detail. The surface morphology of grown SiNWs has been characterized by field emission scanning electron microscopy (FESEM), showing vertical, well aligned SiNWs. Optical absorption and Raman spectroscopy confirmed the presence of the quantum confinement (QC) effect. The EFE performance of the grown nanowire arrays has been examined through recorded J-E measurements under the Fowler-Nordheim framework. The Si NWs grown on p-type Si showed a minimum turn-on field and also a higher field enhancement factor. The band-bending diagram also suggests a lower barrier height of p-type Si NWs compared to n-type Si NWs, which plays a key role in enhancing the EFE performance. These investigations suggest that dopant types (n- and p-types), band gap, crystallite size and stress influence the EFE parameters and Si NWs grown on p-type Si (100) substrates are much more favorable for the investigation of EFE properties.

Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

CHRONIC ANEMIA CAUSED BY GIANT AND SOLITARY PEUTZ-JEGHERS HAMARTOMATOUS POLYP TREATED BY ENDOSCOPIC RESECTION.

•Giant and solitary polyps evolve with anemia. •EUS is an important tool for stage and manage this disease. •Endoscopic treatment is the best treatment choice. •Supplementary video available on this case report.

Hydrolysis of ester phosphates mediated by a copper complex.

Phosphate ester hydrolysis is an important reaction that plays a major role in both enzymatic and non-enzymatic processes, including DNA and pesticide breaking. Although it is a widely studied reaction, the precise mechanistic details, especially for copper complexes, remain under discussion. To contribute to the debate, we present the catalyzed hydrolysis of phosphomono-, di- and tri-esters mediated by the [Cu(II)(1,10-phenanthroline)] complex. The reaction coordinates for several substrates were explored through the metadynamics formalism. Thus, we found that for mono- and di-substituted ester phosphates a concerted mechanism is observed, where a coordinated hydroxyl group attacks the phosphorus atom at the same side as the leaving group, along with a proton transfer. In contrast, tri-substituted phosphate remains coordinated with the metal, and the nucleophile acts independently following an addition-elimination process. That is, the metallic complex achieves a specific nucleophile-phosphate interaction that produces a concerted transition state in the phosphoester hydrolysis process.

Histotripsy induces apoptosis and reduces hypoxia in a neuroblastoma xenograft model.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor of childhood, and high-risk disease is resistant to intensive treatment. Histotripsy is a focused ultrasound therapy under development for tissue ablation via bubble activity. The goal of this study was to assess outcomes of histotripsy ablation in a xenograft model of high-risk NB. METHODS: Female NCr nude mice received NGP-luciferase cells intrarenally. Under ultrasound image guidance, histotripsy pulses were applied over a distance of 4-6 mm within the tumors. Bioluminescence indicative of tumor viability was quantified before, immediately after, and 24 h after histotripsy exposure. Tumors were immunostained to assess apoptosis (TUNEL), endothelium (endomucin), pericytes (αSMA), hypoxia (pimonidazole), vascular endothelial growth factor A (VEGFA), and platelet-derived growth factor-B (PDGF-B). The apoptotic cytokine TNFα and its downstream effector cleaved caspase-3 (c-casp-3) were assessed with SDS-PAGE. RESULTS: Histotripsy induced a 50% reduction in bioluminescence compared to untreated controls, with an absence of nuclei in the treatment core surrounded by a dense rim of TUNEL-positive cells. Tumor regions not targeted by histotripsy also showed an increase in TUNEL staining density. Increased apoptosis in histotripsy samples was consistent with increases in TNFα and c-casp-3 relative to controls. Treated tumors exhibited a decrease in hypoxia, VEGF, PDGF-B, and pericyte coverage of vasculature compared to control samples. Further, increases in vasodilation were found in histotripsy-treated specimens. CONCLUSIONS: In addition to ablative effects, histotripsy was found to drive tumor apoptosis through intrinsic pathways, altering blood vessel architecture, and reducing hypoxia.

Non-viral nitric oxide-based gene therapy improves perfusion and liposomal doxorubicin sonopermeation in neuroblastoma models.

Neuroblastoma (NB) is a pediatric malignancy that accounts for 15% of cancer-related childhood mortality. High-risk NB requires an aggressive chemoradiotherapy regimen that causes significant off-target toxicity. Despite this invasive treatment, many patients either relapse or do not respond adequately. Recent studies suggest that improving tumor perfusion can enhance drug accumulation and distribution within the tumor tissue, potentially augmenting treatment effects without inflicting systemic toxicity. Accordingly, methods that transiently increase tumor perfusion prior to treatment may help combat this disease. Here, we show the use of gene therapy to confer inducible nitric oxide synthase (iNOS) expression solely in the tumor space, using focused ultrasound targeting. NOS catalyzes the reaction that generates nitric oxide (NO), a potent endogenous vasodilator. This study reports the development of a targeted non-viral image-guided platform to deliver iNOS-expressing plasmid DNA (pDNA) to vascular endothelial cells encasing tumor blood vessels. Following transfection, longitudinal quantitative contrast-enhanced ultrasound (qCEUS) imaging revealed an increase in tumor perfusion over 72 h, attributed to elevated intratumoral iNOS expression. Methods: To construct a gene delivery vector, cationic ultrasound-responsive agents (known as "microbubbles") were employed to carry pDNA in circulation and transfect tumor vascular endothelial cells in vivo using focused ultrasound (FUS) energy. This was followed by liposomal doxorubicin (L-DOX) treatment. The post-transfection tumor response was monitored longitudinally using qCEUS imaging to determine relative changes in blood volumes and perfusion rates. After therapy, ex vivo analysis of tumors was performed to examine the bioeffects associated with iNOS expression. Results: By combining FUS therapy with cationic ultrasound contrast agents (UCAs), we achieved selective intratumoral transfection of pDNA encoding the iNOS enzyme. While transitory, the degree of expression was sufficient to induce significant increases in tumoral perfusion, to appreciably enhance the chemotherapeutic payload and to extend survival time in an orthotopic xenograft model. Conclusion: We have demonstrated the ability of a novel targeted non-viral gene therapy strategy to enhance tumor perfusion and improve L-DOX delivery to NB xenografts. While our results demonstrate that transiently increasing tumor perfusion improves liposome-encapsulated chemotherapeutic uptake and distribution, we expect that our iNOS gene delivery paradigm can also significantly improve radio and immunotherapies by increasing the delivery of radiosensitizers and immunomodulators, potentially improving upon current NB treatment without concomitant adverse effects. Our findings further suggest that qCEUS imaging can effectively monitor changes in tumor perfusion in vivo, allowing the identification of an ideal time-point to administer therapy.

How do density functionals affect the Hirshfeld atom refinement?

In this work, the effect of mixing different amounts of Hartree-Fock (HF) exchange with hybrid density functionals applied to the Hirshfeld atom refinement (HAR) of urea and oxalic acid dihydrate is explored. Together, the influence of using different basis sets, methods (including MP2 and HF) and cluster sizes (to model bulk effects) is studied. The results show that changing the amount of HF exchange, no matter the level of theory, has an impact almost exclusively on the H atom refinement parameters. Contrary to pure quantum mechanical calculations where good geometries are obtained with intermediate HF exchange mixtures, in the HAR the best match with neutron diffraction reference values is not necessarily found for these admixtures. While the non-hydrogen covalent bond lengths are insensitive to the combination of method or basis set employed, the X-H bond lengths always increase proportionally to the HF exchange for the analysed systems. This outcome is opposite to what is normally observed from geometry optimisations, i.e., shorter bonds are obtained with greater HF exchange. Additionally, the thermal ellipsoids tend to shrink with larger HF exchange, especially for the H atoms involved in strong hydrogen bonding. Thus, it may be the case that the development of density functionals or basis sets suitable for quantum crystallography should take a different path than those fitted for quantum chemistry calculations.

DNA recognition site of anticancer tinidazole copper(II) complexes.

This paper describes the recognition process of tetrahedral [CuII(tnz)2X2] (X = Cl, Br) complexes by a DNA chain, analyzing the specific interaction between the DNA bases and backbone with the metal and the tinidazole (tnz) ligand. We identified the coordination of the copper metal center with one or two phosphates as the first recognition site for the tinidazole copper(II) complexes, while the ligands present partial intercalation into the minor groove. Also, we discuss a novel trigonal copper(I) tnz bromide complex, obtained by reducing the previously reported [Cu(tnz)2Br2]. This complex sheds light on the mechanism of action of tnz metal complexes as one of the most stable DNA-complex adducts depicts a trigonal geometry around the copper ion.

Prevalence of malnutrition, anemia, and soil-transmitted helminthiasis in preschool-age children living in peri-urban populations in the Peruvian Amazon.

Stunting, anemia, and soil-transmitted helminth (STH) infections are major health concerns for children in extremely poor regions of the world, especially rural and periurban ones. This study aimed to determine the prevalence of these three cooccurring conditions in preschool-age children in an extremely poor district on the outskirts of Iquitos, in the Peruvian Amazon, to inform public health actions. Malnutrition was assessed by standard World Health Organization-recommended metrics; anemia, by hemoglobin levels; and STH, by the Kato-Katz technique. Logistic regression analyses were performed to identify the risk factors for our three outcomes of interest. A total of 572 children aged 6-59 months were recruited in March 2019. We found a 31.3% stunting, 47.2% anemia, and 34.1% STH prevalence. Stunting and anemia figures exceeded both regional and national estimates for 2019. Having more children was a risk factor for stunting, whereas married mothers were associated with a lower risk. Risk factors for anemia included younger age and the male sex, whereas those for STH, older age, incomplete vaccination, and a lower socioeconomic status. Mothers' employment outside the home was also associated with a lower STH risk. This recent evidence highlights the need for prompt and integrated clinical attention and public health actions to address both short- and long-term health consequences in this vulnerable child age group. The integration of a monitoring and evaluation framework is important to effectively manage these conditions, optimize resources and accountability, and show their impact.

How solvent determines the molecular reactive conformation and the selectivity: Solvation spheres and energy.

In solution, the solvent determines the molecular conformation and the chemical reaction viability and selectivity. When solvent-solute and solvent-solvent interactions present similar strengths, explicit salvation is the best way to describe a system. The problem to solve is how big the explicit shell should be. In this paper, we want to answer one of the fundamental questions in the implementation of explicit solvation, exactly how many solvent molecules should be added and where they should be placed. Here we determine the first solvent sphere around a molecule and describe how it controls the conformation and selectivity of a selected reaction. NMR experiments were carried out to identify the number of solvent molecules around the solute that constitutes the first solvent sphere, and the interaction between this solvent sphere and the solute was detected using DFT and QTAIM calculations. A new approach to the solvation energy is presented. Finally, we established the role of solvent molecules in the conformation of the solute and in the transition states that produce the two possible products of the reaction.

Benzene and Borazine, so Different, yet so Similar: Insight from Experimental Charge Density Analysis.

Although benzene and borazine are isoelectronic and isostructural, they have very different electronic structures, mainly due to the polar nature of the B-N bond. Herein, we present an experimental study of the charge density distribution obtained from the multipole model formalism and Hirshfeld atom refinement (HAR) based on high-resolution X-ray diffraction data of borazine B3N3H6 (1) and B,B',B″-trichloroborazine (2) crystals. These data are compared to those obtained from HAR for benzene (4) and 1,3,5-trichlorobenzene (5) and further compared with values obtained from density functional theory calculations in the gas phase, where N,N',N″-trichloroborazine (3) was also included. The results confirm that, unlike benzene, borazines are only weakly aromatic with an island-like electronic delocalization within the B3N3 ring involving only the nitrogen atoms. Furthermore, delocalization indices and interacting quantum atom energy for bonded and non-bonded atoms were found to be highly suitable indicators capable of describing the origin of the discrepancies observed when the degree of aromaticity in 2 and 3 is evaluated using common aromaticity indices. Additionally, analysis of intermolecular interactions in the crystals brings further evidence of a weakly aromatic character of the borazines as it reveals surprising similarities between the crystal packing of borazine and benzene and also between B,B',B″-trichloroborazine and 1,3,5-trichlorobenzene.

Histotripsy Bubble Cloud Contrast With Chirp-Coded Excitation in Preclinical Models.

Histotripsy is a focused ultrasound therapy for tissue ablation via the generation of bubble clouds. These effects can be achieved noninvasively, making sensitive and specific bubble imaging essential for histotripsy guidance. Plane-wave ultrasound imaging can track bubble clouds with an excellent temporal resolution, but there is a significant reduction in echoes when deep-seated organs are targeted. Chirp-coded excitation uses wideband, long-duration imaging pulses to increase signals at depth and promote nonlinear bubble oscillations. In this study, we evaluated histotripsy bubble contrast with chirp-coded excitation in scattering gel phantoms and a subcutaneous mouse tumor model. A range of imaging pulse durations were tested, and compared to a standard plane-wave pulse sequence. Received chirped signals were processed with matched filters to highlight components associated with either fundamental or subharmonic (bubble-specific) frequency bands. The contrast-to-tissue ratio (CTR) was improved in scattering media for subharmonic contrast relative to fundamental contrast (both chirped and standard imaging pulses) with the longest-duration chirped-pulse tested (7.4 [Formula: see text] pulse duration). The CTR was improved for subharmonic contrast relative to fundamental contrast (both chirped and standard imaging pulses) by 4.25 dB ± 1.36 dB in phantoms and 3.84 dB ± 6.42 dB in vivo. No systematic changes were observed in the bubble cloud size or dissolution rate between sequences, indicating image resolution was maintained with the long-duration imaging pulses. Overall, this study demonstrates the feasibility of specific histotripsy bubble cloud visualization with chirp-coded excitation.

Prevalence of malnutrition, anemia, and soil-transmitted helminthiasis in preschool-age children living in peri-urban populations in the Peruvian Amazon / Prevalencia de desnutrición, anemia y helmintiasis transmitida por el contacto con el suelo en niños de edad preescolar que viven en poblaciones periurbanas de la Amazonía peruana / Prevalência de desnutrição, anemia e helmintíase transmitida pelo solo em crianças em idade pré-escolar que vivem em populações periurbanas na Amazônia peruana

Stunting, anemia, and soil-transmitted helminth (STH) infections are major health concerns for children in extremely poor regions of the world, especially rural and periurban ones. This study aimed to determine the prevalence of these three cooccurring conditions in preschool-age children in an extremely poor district on the outskirts of Iquitos, in the Peruvian Amazon, to inform public health actions. Malnutrition was assessed by standard World Health Organization-recommended metrics; anemia, by hemoglobin levels; and STH, by the Kato-Katz technique. Logistic regression analyses were performed to identify the risk factors for our three outcomes of interest. A total of 572 children aged 6-59 months were recruited in March 2019. We found a 31.3% stunting, 47.2% anemia, and 34.1% STH prevalence. Stunting and anemia figures exceeded both regional and national estimates for 2019. Having more children was a risk factor for stunting, whereas married mothers were associated with a lower risk. Risk factors for anemia included younger age and the male sex, whereas those for STH, older age, incomplete vaccination, and a lower socioeconomic status. Mothers' employment outside the home was also associated with a lower STH risk. This recent evidence highlights the need for prompt and integrated clinical attention and public health actions to address both short- and long-term health consequences in this vulnerable child age group. The integration of a monitoring and evaluation framework is important to effectively manage these conditions, optimize resources and accountability, and show their impact.

El retraso en el crecimiento, la anemia y la infección por helmintos transmitidos por el contacto con el suelo (STH) son los principales problemas de salud de la infancia en las regiones del mundo caracterizadas por la extrema pobreza, especialmente en las zonas rurales y periurbanas. Este estudio se llevó a cabo para determinar la prevalencia de estas tres condiciones concurrentes en niños de edad preescolar en un distrito de extrema pobreza en las afueras de Iquitos, en la Amazonía peruana, con el fin último de informar la acción de salud pública. La malnutrición se evaluó mediante las mediciones estándar recomendadas por la Organización Mundial de la Salud (OMS), la anemia mediante los niveles de hemoglobina y la STH mediante la técnica de Kato-Katz. Se realizaron análisis de regresión logística para identificar los factores de riesgo de los tres resultados de interés. Un total de 572 niños de entre 6 y 59 meses fueron reclutados en marzo de 2019. Se determinó que la prevalencia de retraso en el crecimiento era del 31,3%, la anemia del 47,2% y el STH del 34,1%. Las cifras de retraso en el crecimiento y anemia superaron las estimaciones regionales y nacionales para 2019. Tener más hijos fue un factor de riesgo para el retraso del crecimiento, mientras que el hecho de que la madre estuviera casada se asoció con un riesgo menor. Los factores de riesgo para la anemia fueron la edad más joven y el sexo masculino, mientras que los factores de riesgo para el STH fueron la edad más avanzada, las vacunas incompletas y el nivel socioeconómico más bajo. El empleo de las madres fuera del hogar también se asoció a un menor riesgo de STH. Estos datos recientes ponen de manifiesto la necesidad de una atención clínica y una acción de salud pública rápidas e integradas para abordar las consecuencias sanitarias a corto y largo plazo en este grupo de edad infantil vulnerable. La integración de un marco de seguimiento y evaluación sería importante para una gestión eficaz, la optimización de los recursos y la rendición de cuentas, y para demostrar el impacto.

Desnutrição, anemia e infecção por helmintos transmitidos pelo solo (HTS) são as principais preocupações da saúde infantil em regiões do mundo caracterizadas pela extrema pobreza, especialmente em áreas rurais e periurbanas. Realizou-se este estudo para determinar a prevalência dessas três condições coocorrentes em crianças em idade pré-escolar num distrito de extrema pobreza nos arredores de Iquitos, na Amazônia peruana, com a visão final de informar a ação da saúde pública. A desnutrição foi avaliada utilizando métricas padrão recomendadas pela Organização Mundial da Saúde (OMS); a anemia, utilizando níveis de hemoglobina e a HTS, utilizando a técnica Kato-Katz. Realizaram-se análises de regressão logística para identificar fatores de risco para os três desfechos de interesse. Em março de 2019, foram recrutadas 572 crianças de 6 a 59 meses. A prevalência de desnutrição foi determinada em 31,3%, anemia em 47,2% e HTS em 34,1%. Os números de desnutrição e anemia superaram as estimativas regionais e nacionais para 2019. Ter mais filhos foi um fator de risco para a desnutrição, enquanto a mãe ser casada foi associado a um menor risco. Os fatores de risco para anemia foram idade mais jovem e sexo masculino, enquanto os fatores de risco para HTS foram idade mais avançada, vacinação incompleta e menor nível socioeconômico. O emprego das mães fora de casa também foi associado a um menor risco de HTS. Esta evidência recente destaca a necessidade de atenção clínica rápida e integrada e ações da saúde pública para enfrentar as consequências a curto e longo prazo para a saúde nessa faixa etária infantil vulnerável. A integração de um quadro de monitoramento e avaliação seria importante para uma gestão eficaz, otimização de recursos e prestação de contas, e para demonstrar impacto.

Excited state dynamics and photochemistry of nitroaromatic compounds.

Nitrated aromatic molecules have unique photoinduced channels. Due to the presence of oxygen-centered non-bonding orbitals, they can undergo sub-picosecond intersystem crossing showing one of the strongest couplings between the singlet and triplet manifolds among organic molecules. Several nitroaromatic compounds also have a distinctive nitric oxide photodissociation channel which occurs through a complex sequence of atom rearrangements and state changes. These remarkable processes have stimulated the attention of several research groups over the last few years who have applied modern femtosecond spectroscopies and new computational methods to these topics. Nitroaromatic molecules also have demonstrated their value as case-studies, where they can serve to understand the influence of torsional motions between the nitro substituent and the aromatic system in the conversions between states. In this contribution we highlight several of the recent results in this area. Due to the importance of the atmospheric photochemistry of nitrated compounds and their accumulating applications as nitric oxide release agents, continued research about the effects of the different state orderings, substitution patterns, and solvent effects is central to the development of future applications and for a better understanding of their environmental pathways. From this analysis, several pending issues are highlighted, which include the nature of the dominant singlet state involved in intersystem crossing, the role of the formation of charge-transfer states, the yield of the internal conversion channel to the electronic ground state, and a more generalized understanding of the sequence of steps which lead to nitric oxide dissociation.

Intermediate Detection in the Casiopeina-Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction.

A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown that Casiopeina copper complexes caused a dramatic intracellular GSH drop, forming disulfide bonds and reducing CuII to CuI. Herein, through the determination of the [CuII]-SH bond before reduction, we present evidence of the adduct between cysteine and one Casiopeina as an intermediate in the cystine formation and as a model to understand the anticancer activity of copper complexes. Evidence of such an intermediate has never been presented before.

Estimating the mechanical energy of histotripsy bubble clouds with high frame rate imaging.

Mechanical ablation with the focused ultrasound therapy histotripsy relies on the generation and action of bubble clouds. Despite its critical role for ablation, quantitative metrics of bubble activity to gauge treatment outcomes are still lacking. Here, plane wave imaging was used to track the dissolution of bubble clouds following initiation with the histotripsy pulse. Information about the rate of change in pixel intensity was coupled with an analytic diffusion model to estimate bubble size. Accuracy of the hybrid measurement/model was assessed by comparing the predicted and measured dissolution time of the bubble cloud. Good agreement was found between predictions and measurements of bubble cloud dissolution times in agarose phantoms and murine subcutaneous SCC VII tumors. The analytic diffusion model was extended to compute the maximum bubble size as well as energy imparted to the tissue due to bubble expansion. Regions within tumors predicted to have undergone strong bubble expansion were collocated with ablation. Further, the dissolution time was found to correlate with acoustic emissions generated by the bubble cloud during histotripsy insonation. Overall, these results indicate a combination of modeling and high frame rate imaging may provide means to quantify mechanical energy imparted to the tissue due to bubble expansion for histotripsy.

Ancillary Ligand in Ternary CuII Complexes Guides Binding Selectivity toward Minor-Groove DNA.

Copper-containing compounds known as Casiopeínas are biologically active molecules which show promising antineoplastic effects against several cancer types. Two possible hypotheses regarding the mode of action of the Casiopeínas have emerged from the experimental evidence: the generation of reactive oxygen species or the ability of the compounds to bind and interact with nucleic acids. Using robust molecular dynamics simulations, we investigate the interaction of four different Casiopeínas with the DNA duplex d(GCACGAACGAACGAACGC). The studied copper complexes contain either 4-7- or 5-6-substituted dimethyl phenanthroline as the primary ligand and either glycinate or acetylacetonate as the secondary ligand. For statistical significance and to reduce bias in the simulations, four molecules of each copper compound were manually placed at a distance of 10 Å away from the DNA and 20 independent molecular dynamics simulations were performed, each reaching at least 30 µs. This time scale allows us to reproduce expected DNA terminal base-pair fraying and also to observe intercalation/base-pair eversion events generated by the compounds interacting with DNA. The results reveal that the secondary ligand is the guide toward the mode of binding between the copper complex and DNA in which glycinate prefers minor-groove binding and acetylacetonate produces base-pair eversion and intercalation. The CuII complexes containing glycinate interact within the DNA minor groove which are stabilized principally by the hydrogen bonds formed between the amino group of the aminoacidate moiety, whereas the compounds with the acetylacetonate do not present a stable network of hydrogen bonds and the ligand interactions enhance DNA breathing dynamics that result in base-pair eversion.

Do weak interactions affect the biological behavior of DNA? A DFT study of CpG island-like chains.

The origin, stability, and contribution to the formation of noncovalent interactions, such as hydrogen bonds and π - π stacking, have been already widely discussed. However, there are few discussions about the relevance of these weak interactions in DNA performance. In this work, we seek to shed light on the effect of hydrogen bonds and π - π stacking interactions on the biological behavior of DNA through the description of these intermolecular forces in CpG island-like (GC-rich) chains. Furthermore, we made some comparisons with TATA box-like (TA-rich) chains in order to describe hydrogen bond and π - π stacking interactions as a function of the DNA sequence. For hydrogen bonds, we found that there is not a significant effect related to the number of base pairs. Whereas for π - π stacking interactions, the energy tended to decrease as the number of base pairs increased. We observed anticooperative effects for both hydrogen bonds and π - π stacking interactions. These results are in contrast with those of TATA box-like chains since cooperative and additive effects were found for both hydrogen bonds and π - π stacking, respectively. Based on the chemical hardness and density of states, we can conclude that proteins may interact easier with GC-rich chains. We conclude that regardless of the chain length, a protein could interact more easily with these genomics regions because the π - π stacking energies did not increase as a function of the number of base pairs, making, for the first time, a first approximation of the influence of noncovalent interaction on DNA behavior. We did all this work by means of DFT framework included in the DMol3 code (M06-L/DNP). Graphical Abstract Cartoon representation of how nocovalent interactions affect the interaction of DNA with a protein, i.e., how hydrogen bond and π - π stacking interactions influence the biological behavior of DNA.