RESUMO

We present new results on the underlying guest-host interactions and spectral characterization of a CO2 molecule confined in the cages of the sI clathrate hydrate. Such types of porous solids raise computational challenges, as they are of practical interest as gas storage/capture materials. Accordingly, we have directed our efforts toward addressing their modeling in a proper manner, ensuring the quality of the input data and the efficiency of the computational approaches. The computational procedure for spectral simulations, within the multi-configurational time-dependent Hartree framework, involves the development of a fully coupled Hamiltonian, including an exact kinetic energy operator and a many-body representation of the potential, along with dipole moment surfaces, both obtained through neural network machine learning techniques. The resulting models were automatically trained and tested on extensive datasets generated by PW86PBE-XDM calculations, following the outcome of previous benchmark studies. Our simulations enable us to explore various aspects of the quantized dynamics upon confinement of CO2@D/T, such as constrained rotational-translational quantum motions and the averaged position/orientation of the CO2 guest in comparison to the experimental data available. Particularly notable are the distinct energy patterns observed in the computed spectra for the confined CO2 in the D and T cages, with a considerably high rotational-translational coupling in the CO2@T case. Leveraging reliable computations has proved instrumental, highlighting the sensitivity of the spectral features to the shape and strength of the potential interactions, with the explicit description of many-body contributions being significant.

RESUMO

Trypanosomatids are an important group of parasites that predominate in tropical and subtropical areas of the planet, which cause diseases that are classified as forgotten and neglected by the world health organization. In this group of parasites, we find Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense and Leishmania spp, for which there is no vaccine available, and its control has focused mainly on pharmacological treatment. Due to the poverty situation where these diseases are found and the biological complexity of these parasites, there are multiple variables to control, including the diversity of species, the complexity of their life cycles, drug resistance, cytotoxicity, the limited use in pregnant women, the high costs of treatment and the little-known pharmacological mechanisms of action, among others. It is therefore necessary to find new strategies and approaches for the treatment of these parasitic diseases. Among these new approaches is the rational search for new targets based on the allosteric inhibition of protein kinases, which have been little studied in trypanosomatids. Among these kinases, we find Glycogen Synthase Kinase-3 (GSK-3), a kinase of great pharmacological interest, which is under intense basic and clinical research by pharmaceutical companies for the treatment of cancer. This kinase, highly studied in the PI3K/AKT/mTOR pathway signaling in humans, has an orthologous gene in these parasites (GSK-3 s), which has proven to be essential for them in response to different challenges; Therefore, it is notable to increase research in this kinase in order to achieve a broad structural and functional characterization in the different species of trypanosomatids.

Assuntos

RESUMO

ABSTRACT Trypanosomatids are an important group of parasites that predominate in tropical and subtropical areas of the planet, which cause diseases that are classified as forgotten and neglected by the world health organization. In this group of parasites, we find Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense and Leishmania spp, for which there is no vaccine available, and its control has focused mainly on pharmacological treatment. Due to the poverty situation where these diseases are found and the biological complexity of these parasites, there are multiple variables to control, including the diversity of species, the complexity of their life cycles, drug resistance, cytotoxicity, the limited use in pregnant women, the high costs of treatment and the little-known pharmacological mechanisms of action, among others. It is therefore necessary to find new strategies and approaches for the treatment of these parasitic diseases. Among these new approaches is the rational search for new targets based on the allosteric inhibition of protein kinases, which have been little studied in trypanosomatids. Among these kinases, we find Glycogen Synthase Kinase-3 (GSK-3), a kinase of great pharmacological interest, which is under intense basic and clinical research by pharmaceutical companies for the treatment of cancer. This kinase, highly studied in the PI3K/AKT/mTOR pathway signaling in humans, has an orthologous gene in these parasites (GSK-3 s), which has proven to be essential for them in response to different challenges; Therefore, it is notable to increase research in this kinase in order to achieve a broad structural and functional characterization in the different species of trypanosomatids.

RESUMO

We report new results on the translational-rotational (T-R) states of the CO2 molecule inside the sI clathrate-hydrate cages. We adopted the multiconfiguration time-dependent Hartree methodology to solve the nuclear molecular Hamiltonian, and to address issues on the T-R couplings. Motivated by experimental X-ray observations on the CO2 orientation in the D and T sI cages, we aim to evaluate the effect of the CO2 -water interaction on quantum dynamics. Thus, we first compared semiempirical and ab initio-based pair interaction model potentials against first-principles DFT-D calculations for ascertaining the importance of nonadditive many-body effects on such guest-host interactions. Our results reveal that the rotational and translational excited states quantum dynamics is remarkably different, with the pattern and density of states clearly affected by the underlying potential model. By analyzing the corresponding the probability density distributions of the calculated T-R eigenstates on both semiempirical and ab initio pair CO2 -water nanocage potentials, we have extracted information on the altered CO2 guest local structure, and we discussed it in connection with experimental data on the orientation of the CO2 molecule in the D and T sI clathrate cages available from neutron diffraction and 13 C solid-state NMR studies, as well as in comparison with previous molecular dynamics simulations. Our calculations provide a very sensitive test of the potential quality by predicting the low-lying T-R states and corresponding transitions for the encapsulated CO2 molecule. As such spectroscopic observables have not been measured so far, our results could trigger further detailed experimental and theoretical investigations leading to a quantitative description of the present guest-host interactions.

RESUMO

We introduce an efficient quantum fully coupled computational scheme within the multiconfiguration time-dependent Hartree (MCTDH) approach to handle the otherwise extremely costly computations of translational-rotational-vibrational states and energies of light-molecule endofullenes. Quantum calculations on energy levels are reported for a water molecule inside C60 fullerene by means of such a systematic approach that includes all nine degrees of freedom of H2O@C60 and does not consider restrictions above them. The potential energy operator is represented as a sum of natural potentials employing the n-mode expansion, along with the exact kinetic energy operator, by introducing a set of Radau internal coordinates for the H2O molecule. On the basis of the present rigorous computations, various aspects of the quantized intermolecular dynamics upon confinement of H2O@C60 are discussed, such as the rotational energy level splitting and the significant frequency shifts of the encapsulated water molecule vibrations. The impact of water encapsulation on quantum features is explored, and insights into the nature of the underlying forces are provided, highlighting the importance of a reliable first-principles description of the guest-host interactions.

RESUMO

We present 15-dimensional quantum multiconfiguration time-dependent Hartree calculations of the vibrational levels of the He5 I2 van der Waals (vdW) complex employing an ab initio-based potential energy surface (PES). The energies and spatial features of such bound structures are analyzed, providing predictions on the structures and relative stabilities of its three lowest isomers. We found that the most stable isomer corresponds to all five He atoms encircling the I2 molecule, indicating that in this case the anharmonic quantum effects do not stabilize the isomers involving a He atom in a linear configuration as reported previously for the smaller HeN I2 systems. Such finding provides information on the overall structuring of the finite-size-solvent systems, highlighting the intriguing interplay between weak intermolecular interactions and quantum effects. © 2019 Wiley Periodicals, Inc.

RESUMO

We implemented a systematic procedure for treating the quantal rotations by including all translational and vibrational degrees of freedom for any triatomic bent molecule in any embedded or confined environment, within the MCTDH framework. Fully coupled quantum treatments were employed to investigate unconventional properties in nanoconfined molecular systems. In this way, we facilitate a complete theoretical analysis of the underlying dynamics that enables us to compute the energy levels and the nuclear spin isomers of a single water molecule trapped in a C60 fullerene cage. The key point lies in the full 9D description of both nuclear and electronic degrees of freedom, as well as a reliable representation of the guest-host interaction. The presence of occluded impurities or inhomogeneities due to noncovalent interactions in the interfullerene environment could modify aspects of the potential, causing significant coupling between otherwise uncoupled modes. Using specific n-mode model potentials, we obtained splitting patterns that confirm the effects of symmetry breaking observed by experiments in the ground ortho-H2O state. Further, our investigation reveals that the first rotationally excited states of the encapsulated ortho- and para-H2O have also raised their 3-fold degeneracy. In view of the complexity of the problem, our results highlight the importance of accurate and computational demanding approaches for building up predictive models for such nanoconfined molecules.

RESUMO

Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca2+]i) homeostasis. It has been suggested that oxidative stress may be involved in this process. We and others have reported that in cardiomyopathies the NADPH oxidase (NOX)-derived superoxide is increased, with a negative impact on [Ca2+]i and contractility. We tested the hypothesis that in the aged heart, [Ca2+]i handling and contractility are disturbed by NOX-derived superoxide. For this we used adults (≈5 month-old) and aged (20⁻24 month-old) rats. Contractility was evaluated in isolated hearts, challenged with isoproterenol. To assess [Ca2+]i, isolated cardiac myocytes were field-stimulated and [Ca2+]i was monitored with fura-2. Cardiac concentration-response to isoproterenol was depressed in aged compared to adults hearts (p < 0.005), but was restored by NOX inhibitors apocynin and VAS2870. In isolated cardiomyocytes, apocynin increased the amplitude of [Ca2+]i in aged myocytes (p < 0.05). Time-50 [Ca2+]i decay was increased in aged myocytes (p < 0.05) and reduced towards normal by NOX inhibition. In addition, we found that myofilaments Ca2+ sensitivity was reduced in aged myocytes (p < 0.05), and was further reduced by apocynin. NOX2 expression along with NADPH oxidase activity was increased in aged hearts. Phospholamban phosphorylation (Ser16/Thr17) after isoproterenol treatment was reduced in aged hearts compared to adults and was restored by apocynin treatment (p < 0.05). In conclusion, ß-adrenergic-induced contractility was depressed in aged hearts, and NOX inhibition restored back to normal. Moreover, altered Ca2+ handling in aged myocytes was also improved by NOX inhibition. These results suggest a NOX-dependent effect in aged myocytes at the level of Ca2+ handling proteins and myofilaments.

Assuntos

RESUMO

The multiconfiguration time-dependent Hartree (MCTDH) method using a six-dimensional Hamiltonian that includes all rotational and vibrational degrees of freedom and an ab initio potential energy surface was employed to calculate the rovibronic states of the HeBr2 van der Waals complex. All rotational states of energies within 7 cm -1 with respect to the energy of the linear ground state were calculated without restriction of the total angular momentum. In total, we obtained 500 and 320 rotationally excited states of the ground vibrational T-shaped and linear isomers of the HeBr2, respectively, and compared them with those predicted by the rigid rotor model. A thermodynamic model was then introduced to determine the relative stability of the two conformers as a function of the temperature. On the basis of the present results, the linear conformers were found to be energetically more stable than the T-shaped ones by 1.14 cm-1 at T = 0 K, whereas conversion from linear to T-shaped complexes was observed at temperatures above 2.87 K.

RESUMO

The structure and relative stability of higher-order He3,4I2 clusters are investigated by carrying out full-dimensional quantum calculations within the multiconfiguration time-dependent Hartree framework. The full interaction between the I2 molecule and the He atoms is based on analytical three-body ab initio He-I2 potentials obtained from high level ab initio calculations plus the He-He interaction. The low-lying minima on the potential surfaces are found to be very close in energy with the He atoms in a ring encircling the dopant for the global minimum structure, while for the local minima one or two of the He atoms prefer the linear arrangements along the I2-axis. Such classical description on the basis of the potential energy landscape is corrected by including anharmonic quantum effects, present in highly floppy systems, by carrying out full dimensional quantum calculations. The potential energy operator was constructed by natural potential fits, while a mode combination scheme was employed to optimize the computational cost of the improved relaxation calculations. The obtained results predict the relative stability of the He3,4I2 isomers at zero temperature and provide benchmark data on binding energies and structural properties of these van der Waals systems. The (2,1) and (2,2), involving two He atoms in the T-shape and one or two He atoms in the linear configurations, respectively, are found to be the most stable isomers, although extremely close in energy with the (3,0) and (4,0) ones as predicted by classical optimizations. Comparison with experimental data on similar systems at low temperatures is also discussed. This analysis indicates once more the importance of quantum delocalization and the need of accurate quantum-mechanical treatments to characterize such doped helium nanosystems.