Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor.

Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.

Predicting hidden bulk phases from surface phases in bilayered Sr3Ru2O7.

The ability to predict hidden phases under extreme conditions is not only crucial to understanding and manipulating materials but it could also lead to insight into new phenomena and novel routes to synthesize new phases. This is especially true for Ruddlesden-Popper perovskite phases that possess interesting properties ranging from superconductivity and colossal magnetoresistance to photovoltaic and catalytic activities. In particular, the physical properties of the bilayer perovskite Sr3Ru2O7 at the surface are intimately tied to the rotation and tilt of the RuO6 octahedra. To take advantage of the extra degree of freedom associated with tilting we have performed first principles hybrid density functional simulations of uniaxial pressure applied along the c-axis of bulk Sr3Ru2O7 where we find that the octahedra become tilted, leading to two phase transitions. One is a structural transition at [Formula: see text]1.5 GPa, and the other is from a ferromagnetic (FM) metal to an antiferromagnetic (AFM) insulator at [Formula: see text]21 GPa whose AFM spin configuration is different from the AFM state near the FM ground state.

Revisiting the zero-temperature phase diagram of stoichiometric SrCoO3 with first-principles methods.

By using first-principles methods based on density functional theory we revisited the zero-temperature phase diagram of stoichiometric SrCoO3, a ferromagnetic metallic perovskite that undergoes significant structural, electronic, and magnetic changes as its content of oxygen is decreased. We considered both bulk and epitaxial thin film geometries. In the bulk case, we found that a tetragonal P4/mbm phase with moderate Jahn-Teller distortions and a c/a ratio of is consistently predicted to have a lower energy than the thus far assumed ground-state cubic Pm3[combining macron]m phase. In thin films, we found two phase transitions occurring at compressive and tensile epitaxial strains. However, in contrast to previous theoretical predictions, our results show that: (i) the phase transition induced by tensile strain is isostructural and involves only a change in magnetic spin order (that is, not a metallic to insulator transformation), and (ii) the phase transition induced by compressive strain comprises simultaneous structural, electronic and magnetic spin order changes, but the required epitaxial stress is so large (<-6%) that is unlikely to be observed in practice. Our findings call for a revision of the crystallographic data obtained in fully oxidised SrCoO3 samples at low temperatures, as well as of previous first-principles studies.

Systematic pseudopotentials from reference eigenvalue sets for DFT calculations: Pseudopotential files.

We present in this article a pseudopotential (PP) database for DFT calculations in the context of the SIESTA code [1-3]. Comprehensive optimized PPs in two formats (psf files and input files for ATM program) are provided for 20 chemical elements for LDA and GGA exchange-correlation potentials. Our data represents a validated database of PPs for SIESTA DFT calculations. Extensive transferability tests guarantee the usefulness of these PPs.

Intrinsic Defects, Fluctuations of the Local Shape, and the Photo-Oxidation of Black Phosphorus.

Black phosphorus is a monatomic semiconducting layered material that degrades exothermically in the presence of light and ambient contaminants. Its degradation dynamics remain largely unknown. Even before degradation, local-probe studies indicate non-negligible local curvature-through a nonconstant height distribution-due to the unavoidable presence of intrinsic defects. We establish that these intrinsic defects are photo-oxidation sites because they lower the chemisorption barrier of ideal black phosphorus (>10 eV and out of visible-range light excitations) right into the visible and ultraviolet range (1.6 to 6.8 eV), thus enabling photoinduced oxidation and dissociation of oxygen dimers. A full characterization of the material's shape and of its electronic properties at the early stages of the oxidation process is presented as well. This study thus provides fundamental insights into the degradation dynamics of this novel layered material.

Predicting singlet-triplet energy splittings with projected Hartree-Fock methods.

Hartree-Fock (HF) and density functional theory (DFT) methods are known for having problems in predicting singlet-triplet energy splittings when the system displays significant diradical character. Multireference methods are traditionally advocated to deal with the spin-contamination problem inherent in broken-symmetry mean-field methods. In the present work, spin-contamination is rigorously eliminated by means of a symmetry projection approach, carried out in a variation-after-projection fashion, recently implemented in our research group. We here explore the performance of a variety of projected Hartree-Fock (PHF) approaches (SUHF, KSUHF, SGHF, and KSGHF) in predicting singlet-triplet energy gaps in a broad set of diradical systems: small diatomic molecules, carbenes and silenes, and a few larger molecules (trimethylenemethane and benzyne isomers). For most of these systems, accurate experimental data is available in the literature. Additionally, we assess the quality of the geometrical parameters obtained in SUHF-based optimizations for some of the systems considered. Our results indicate that PHF methods yield high-quality multireference wave functions, providing a good description of the ground state potential surface as well as an accurate singlet-triplet splitting gap, all within a modest mean-field computational cost.

Entanglement and polyradical character of polycyclic aromatic hydrocarbons predicted by projected Hartree-Fock theory.

We study strong correlation effects in a series of fused benzene rings (acenes) of varying length and width using our recently developed projected Hartree-Fock (PHF) method. These molecules, commonly known as polycyclic aromatic hydrocarbons or nanographenes, are very challenging for electronic structure theory because of their strong multireference character. This challenge is here met by PHF at moderate computational cost optimizing a spin eigenfunction obtained by projection of an unrestricted Hartree-Fock (UHF) trial determinant. The resulting method, known as SUHF, predicts that polyradical behavior and orbital entanglement are enhanced with molecular size, especially in systems whose structural motifs are dominated by zigzag edges, like oligoacenes.

High insoluble fibre content increases in vitro starch digestibility in partially baked breads.

Wheat breads prepared from frozen partially baked breads were characterized by their content of rapidly digestible starch (RDS) and slowly digestible starch (SDS) by the in vitro starch digestibility method developed by Englyst. Breads with different contents and types of fibre and breads prepared with different fermentation processes were studied. Bread with inulin and with a double fermentation had the lowest RDS content of 58.8 ± 1.7 and 60.0 ± 1.9 (% dry matter), respectively. Wheat bran bread, seeded bread, triple fermentation white bread and baguette-type bread showed values of RDS between 63.1 ± 1.7 and 65.7 ± 1.7 with no significant differences between them (p < 0.05). The fraction of SDS was higher in wheat breads than in breads with added fibre. The highest values of the starch digestive rate index (SDRI) were obtained by the three types of breads with added fibre, which ranged from 91.8 ± 3.5 to 95.8 ± 3.5 versus 80.2 ± 3.5 to 87.5 ± 3.5 for white wheat breads. A significant (p < 0.01) positive linear correlation between the insoluble fibre content and SDRI was obtained (R² = 0.96). Insoluble fibre dilutes and disrupts gluten network and probably weakens the interaction between gluten and starch, which protects starch from digestive enzymes action. Scanning electronic microscopy microstructure of bread crumbs corroborated this statement.

Electronic structure of HgBa2Ca(n-1)Cu(n)O(2n+2) (n = 1, 2, 3) superconductor parent compounds from periodic hybrid density functional theory.

The electronic structure of HgBa(2)Ca(n) (-1)Cu(n)O(2n+2) (n = 1, 2, and 3) high T(c) superconductor parent compounds has been investigated by means of periodic hybrid density functional theory. Similar to other cuprates, these materials are predicted to exhibit an antiferromagnetic ground state with well localized S = 1/2 magnetic centers at the Cu(2+) sites. However, the presence of the HgO(2) structural units largely defines the nature of states dominating the energy range around Fermi energy. This results in a complex charge transfer character of the insulating gap which decreases when increasing the number of CuO(2) planes in the unit cell, to the point that in the HgBa(2)Ca(2)Cu(3)O(8) compound it becomes so small that one can claim that the resulting material is metallic. Nevertheless, the metallic character arises from the HgO(2) structural units and coexists with the antiferromagnetic order arising from the localized spins at the Cu(2+) sites.

Performance of plane-wave-based LDA+U and GGA+U approaches to describe magnetic coupling in molecular systems.

This work explores the performance of periodic plane wave density functional theory calculations with an on-site Coulomb correction to the standard LDA and GGA exchange-correlation potential--commonly used to describe strongly correlated solids--in describing the magnetic coupling constant of a series of molecular compounds representative of dinuclear Cu complexes and of organic diradicals. The resulting LDA+U or GGA+U formalisms, lead to results comparable to experiment and to those obtained by means of standard hybrid functionals provided that the value of the U parameter is adequately chosen. Hence, these methods offer an alternative efficient computational scheme to correct LDA and GGA approaches to adequately describe the electronic structure and magnetic coupling in large molecular magnetic systems, although at the expenses of introducing an empirical (U) parameter. For all investigated copper dinuclear systems, the LDA+U and GGA+U approaches lead to an improvement in the description of magnetic properties over the original LDA and GGA schemes with an accuracy similar to that arising from the hybrid B3LYP functional, by increasing the on-site Coulomb repulsion with a moderate U value. Nevertheless, the introduction of an arbitrary U value in the 0-10 eV range most often provides the correct ground-state spin distribution and the correct sign of the magnetic coupling constant.

Reliability of range-separated hybrid functionals for describing magnetic coupling in molecular systems.

The performance of the Heyd-Scuseria-Ernzerhorf (HSE) and single parameter long-range corrected Perdew-Burke-Ernzerhorf (LC-omegaPBE) range-separated hybrids for predicting magnetic coupling constants has been investigated for a broad set of magnetic molecular systems for which accurate experimental data exist. The set includes the H-He-H model system, two organic diradicals with different magnetic behaviors, and a series of Cu dinuclear complexes with a broad range of magnetic coupling values. Both HSE and LC-omegaPBE provide a significant improvement to standard hybrids such as the well-known hybrid Becke-3-parameters exchange with Lee-Yang-Parr correlation (B3LYP) functional. Nevertheless, the performance of these two range-separated hybrid functionals is different: HSE overestimates antiferromagnetic and ferromagnetic interactions in Cu dinuclear complexes (although significantly less than B3LYP), whereas LC-omegaPBE treats ferro- and antiferromagnetic couplings on a much more balanced way. The increased accuracy of LC-omegaPBE suggests that the inclusion of 100% Hartree-Fock exchange considered in the definition of this long-range corrected hybrid functional has important consequences for an accurate description of exchange and correlation effects on the electronic structure of open shell systems. On the other hand, HSE, which was developed with periodic systems in mind, also performs quite well (and better than B3LYP) thus opening the possibility of magnetic coupling studies in metal oxides and other challenging solids.