Design and Performance Analysis of a Constellation of Nanosatellites to Monitor Water Quality in the Southern Catchment of the Baltic Sea.

The quality of inland waters has a significant influence on human life and the functioning of the environment. The disasters that result from water pollution may cause major financial losses and lead to irreversible changes in the ecosystem, such as the dying out of endemic species of plants and animals. Quick detection of pollution sources may minimise those negative effects and reduce the costs of their elimination. The study presents a constellation design that provides imagery in the optic range and that might supplement the point water quality measurements that are conducted in situ. The area of interest was the southern catchment of the Baltic Sea and the main rivers in the region. The requirements for the designed mission were defined in reference to the remote sensing needs concerning the monitoring of water quality, the characteristics of the analysed area, and weather conditions. Based on these requirements, the Simera Sense MultiScape100 CIS sensor and the M6P nanosatellite manufactured by NanoAvionics were selected. The authors proposed a process for selecting the optimum orbit, taking into account the area of interest, the possibilities of the satellite platform, and of the sensor's optics. As a result of the analyses, four concepts of creating a constellation were presented. Each constellation consisted of four nanosatellites. The designs were then subjected to performance analysis, considering the lighting limitations. Among the proposed systems, the constellation designed by the authors was distinguished; it used four orbital planes and achieved the coverage and availability of imagery in the time that was best suited to monitoring the waters. Thanks to a small number of platforms, the costs of the mission are relatively low, and it might significantly improve awareness of the current state of surface waters in the southern catchment of the Baltic Sea.

Implications of Additivity and Nonadditivity for Machine Learning and Deep Learning Models in Drug Design.

Matched molecular pairs (MMPs) are nowadays a commonly applied concept in drug design. They are used in many computational tools for structure-activity relationship analysis, biological activity prediction, or optimization of physicochemical properties. However, until now it has not been shown in a rigorous way that MMPs, that is, changing only one substituent between two molecules, can be predicted with higher accuracy and precision in contrast to any other chemical compound pair. It is expected that any model should be able to predict such a defined change with high accuracy and reasonable precision. In this study, we examine the predictability of four classical properties relevant for drug design ranging from simple physicochemical parameters (log D and solubility) to more complex cell-based ones (permeability and clearance), using different data sets and machine learning algorithms. Our study confirms that additive data are the easiest to predict, which highlights the importance of recognition of nonadditivity events and the challenging complexity of predicting properties in case of scaffold hopping. Despite deep learning being well suited to model nonlinear events, these methods do not seem to be an exception of this observation. Though they are in general performing better than classical machine learning methods, this leaves the field with a still standing challenge.

Intermolecular interactions of the extended recognition site of VIM-2 metallo-ß-lactamase with 1,2,4-triazole-3-thione inhibitors. Validations of a polarizable molecular mechanics potential by ab initio QC.

Molecular dynamics on the complexes of inhibitors with Zn-metalloproteins are a privileged area of applications of polarizable molecular mechanics potentials. With which accuracy could these reproduce the QC intermolecular interaction energies in the two mono-zinc cores and in the dizinc core, toward full-fledged MD simulations on the entire protein complexes? We considered the complexes of the extended recognition site of a Zn-dependent metallo-ß-lactamase, VIM-2, produced by bacteria responsible for nosocomial infections, with five newly synthesized inhibitors sharing an original dizinc binding group, 1,2,4-triazole-3-thione (TZT). We considered the energy-minimized structures of each of the five VIM-2 complexes obtained with the SIBFA potential. Energy decomposition analyses (EDA) at the HF level enabled to compare the QC and the SIBFA ΔE values and their contributions in the zinc cores, with and without TZT, totaling 30 complexes. With one exception, the ΔE(QC) values were reproduced with relative errors <1.5%. We next considered the complex of the entire inhibitors with an extended model of VIM-2 recognition site, totaling up to 280 atoms. ΔE(SIBFA) could closely reproduce ΔE(QC). EDA analyses were resumed on the complexes of each inhibitor arm with its interacting VIM-2 residues. As a last step, EDA results at correlated levels were analyzed for the mono- and dizinc sites enabling comparisons with dispersion-augmented ΔE(SIBFA) and correlated multipoles and polarizabilities. Closely reproducing ΔE(QC) and the contrasting trends of its individual contributions should enable for dependable free energy perturbation studies and comparisons to recent experimental ΔG values, limiting as much as possible the reliance on error compensations.

4-Amino-1,2,4-triazole-3-thione-derived Schiff bases as metallo-ß-lactamase inhibitors.

Resistance to ß-lactam antibiotics in Gram-negatives producing metallo-ß-lactamases (MBLs) represents a major medical threat and there is an extremely urgent need to develop clinically useful inhibitors. We previously reported the original binding mode of 5-substituted-4-amino/H-1,2,4-triazole-3-thione compounds in the catalytic site of an MBL. Moreover, we showed that, although moderately potent, they represented a promising basis for the development of broad-spectrum MBL inhibitors. Here, we synthesized and characterized a large number of 4-amino-1,2,4-triazole-3-thione-derived Schiff bases. Compared to the previous series, the presence of an aryl moiety at position 4 afforded an average 10-fold increase in potency. Among 90 synthetic compounds, more than half inhibited at least one of the six tested MBLs (L1, VIM-4, VIM-2, NDM-1, IMP-1, CphA) with Ki values in the µM to sub-µM range. Several were broad-spectrum inhibitors, also inhibiting the most clinically relevant VIM-2 and NDM-1. Active compounds generally contained halogenated, bicyclic aryl or phenolic moieties at position 5, and one substituent among o-benzoic, 2,4-dihydroxyphenyl, p-benzyloxyphenyl or 3-(m-benzoyl)-phenyl at position 4. The crystallographic structure of VIM-2 in complex with an inhibitor showed the expected binding between the triazole-thione moiety and the dinuclear centre and also revealed a network of interactions involving Phe61, Tyr67, Trp87 and the conserved Asn233. Microbiological analysis suggested that the potentiation activity of the compounds was limited by poor outer membrane penetration or efflux. This was supported by the ability of one compound to restore the susceptibility of an NDM-1-producing E. coli clinical strain toward several ß-lactams in the presence only of a sub-inhibitory concentration of colistin, a permeabilizing agent. Finally, some compounds were tested against the structurally similar di-zinc human glyoxalase II and found weaker inhibitors of the latter enzyme, thus showing a promising selectivity towards MBLs.

Calibration of 1,2,4-Triazole-3-Thione, an Original Zn-Binding Group of Metallo-ß-Lactamase Inhibitors. Validation of a Polarizable MM/MD Potential by Quantum Chemistry.

In the context of the SIBFA polarizable molecular mechanics/dynamics (PMM/PMD) procedure, we report the calibration and a series of validation tests for the 1,2,4-triazole-3-thione (TZT) heterocycle. TZT acts as the chelating group of inhibitors of dizinc metallo-ß-lactamases (MBL), an emerging class of Zn-dependent bacterial enzymes, which by cleaving the ß-lactam bond of most ß-lactam antibiotics are responsible for the acquired resistance of bacteria to these drugs. Such a study is indispensable prior to performing PMD simulations of complexes of TZT-based inhibitors with MBL's, on account of the anchoring role of TZT in the dizinc MBL recognition site. Calibration was done by comparisons to energy decomposition analyses (EDA) of high-level ab initio QC computations of the TZT complexes with two probes: Zn(II), representative of "soft" dications, and water, representative of dipolar molecules. We performed distance variations of the approach of each probe to each of the two TZT atoms involved in Zn ligation, the S atom and the N atom ortho to it, so that each SIBFA contribution matches its QC counterpart. Validations were obtained by performing in- and out-of-plane angular variations of Zn(II) binding in monoligated Zn(II)-TZT complexes. The most demanding part of this study was then addressed. How well does ΔE(SIBFA) and its individual contributions compare to their QC counterparts in the dizinc binding site of one MBL, L1, whose structure is known from high-resolution X-ray crystallography? Six distinct complexes were considered, namely each separate monozinc site, and the dizinc site, whether ligated or unligated by TZT. Despite the large magnitude of the interaction energies, in all six complexes ΔE(SIBFA) can match ΔE(QC) with relative errors <2% and the proper balance of individual energy contributions. The computations were extended to the dizinc site of another MBL, VIM-2, and its complexes with two other TZT analogues. ΔE(SIBFA) faithfully reproduced ΔE(QC) in terms of magnitude, ranking of the three ligands, and trends of the separate energy contributions. A preliminary extension to correlated calculations is finally presented. All these validations should enable a secure design of a diversity of TZT-containing MBL inhibitors: a structurally and energetically correct anchoring of TZT should enable all other inhibitor groups to in turn optimize their interactions with the other target MBL residues.

Importance of explicit smeared lone-pairs in anisotropic polarizable molecular mechanics. Torture track angular tests for exchange-repulsion and charge transfer contributions.

A correct representation of the short-range contributions such as exchange-repulsion (Erep ) and charge-transfer (Ect ) is essential for the soundness of separable, anisotropic polarizable molecular mechanics potentials. Within the context of the SIBFA procedure, this is aimed at by explicit representations of lone pairs in their expressions. It is necessary to account for their anisotropic behaviors upon performing not only in-plane, but also out-of-plane, variations of a probe molecule or cation interacting with a target molecule or molecular fragment. Thus, Erep and Ect have to reproduce satisfactorily the corresponding anisotropies of their quantum chemical (QC) counterparts. A significant improvement of the out-of-plane dependencies was enabled when the sp2 and sp localized lone-pairs are, even though to a limited extent, delocalized on both sides of the plane, above and below the atom bearer but at the closely similar angles as the in-plane lone pair. We report calibration and validation tests on a series of monoligated complexes of a probe Zn(II) cation with several biochemically relevant ligands. Validations are then performed on several polyligated Zn(II) complexes found in the recognition sites of Zn-metalloproteins. Such calibrations and validations are extended to representative monoligated and polyligated complexes of Mg(II) and Ca(II). It is emphasized that the calibration of all three cations was for each ΔE contribution done on a small training set bearing on a limited number of representative N, O, and S monoligated complexes. Owing to the separable nature of ΔE, a secure transferability is enabled to a diversity of polyligated complexes. For these the relative errors with respect to the target ΔE(QC) values are generally < 3%. Overall, the article proposes a full set of benchmarks that could be useful for force field developers. © 2017 Wiley Periodicals, Inc.

Sites for methane activation on lithium-doped magnesium oxide surfaces.

Density functional calculations yield energy barriers for H abstraction by oxygen radical sites in Li-doped MgO that are much smaller (12±6 kJ mol(-1)) than the barriers inferred from different experimental studies (80-160 kJ mol(-1)). This raises further doubts that the Li(+)O(˙-) site is the active site as postulated by Lunsford. From temperature-programmed oxidative coupling reactions of methane (OCM), we conclude that the same sites are responsible for the activation of CH4 on both Li-doped MgO and pure MgO catalysts. For a MgO catalyst prepared by sol-gel synthesis, the activity proved to be very different in the initial phase of the OCM reaction and in the steady state. This was accompanied by substantial morphological changes and restructuring of the terminations as transmission electron microscopy revealed. Further calculations on cluster models showed that CH4 binds heterolytically on Mg(2+)O(2-) sites at steps and corners, and that the homolytic release of methyl radicals into the gas phase will happen only in the presence of O2.

Energetics of Water Oxidation Catalyzed by Cobalt Oxide Nanoparticles: Assessing the Accuracy of DFT and DFT+U Approaches against Coupled Cluster Methods.

Some of the most promising catalysts for water oxidation rely on crystalline and amorphous cobalt oxide nanoparticles. Density functional theory (DFT) calculations are routinely used to study the electronic and atomic structures of these materials as well as the thermodynamics and mechanisms of the electrochemical oxygen evolution reaction. The accuracy of these theoretical predictions has never been compared to high-level quantum chemistry methods. We perform coupled cluster (CC) quantum chemistry calculations on model cobalt oxide surface sites and use them to benchmark the accuracy of the most popular exchange and correlation functionals. Hybrid B3LYP and PBE0 functionals lead to fair agreement with the CC energies, while standard gradient-corrected functionals show important discrepancies. The inclusion of on-site electronic repulsion (DFT+U) substantially improves the calculated electronic and structural properties, but no value of the U parameter reproduces the CC results. We discuss the implications of these findings for amorphous cobalt phosphate nanoparticles, showing that the reactivity of these catalysts is not altered by surface phosphate groups.

Structure determination of neutral MgO clusters--hexagonal nanotubes and cages.

Structural information for neutral magnesium oxide clusters has been obtained by a comparison of their experimental vibrational spectra with predictions from theory. (MgO)(n) clusters with n = 3-16 have been studied in the gas phase with a tunable IR-UV two-color ionization scheme and size-selective infrared spectra have been measured. These IR spectra are compared to the calculated spectra of the global minimum structures predicted by a hybrid ab initio genetic algorithm. The comparison shows clear evidence that clusters of the composition (MgO)(3k) (k = 1-5) form hexagonal tubes, which confirm previous theoretical predictions. For the intermediate sizes (n≠ 3k) cage-like structures containing hexagonal (MgO)(3) rings are identified. Except for the cubic (MgO)(4) no evidence for bulk like structures is found.

Preferential activation of primary C-H bonds in the reactions of small alkanes with the diatomic MgO(+*) cation.

The C-H bond activation of small alkanes by the gaseous MgO(+*) cation is probed by mass spectrometric means. In addition to H-atom abstraction from methane, the MgO(+*) cation reacts with ethane, propane, n- and iso-butane through several pathways, which can all be assigned to the occurrence of initial C-H bond activations. Specifically, the formal C-C bond cleavages observed are assigned to C-H bond activation as the first step, followed by cleavage of a beta-C-C bond concomitant with release of the corresponding alkyl radical. Kinetic modeling of the observed product distributions reveals a high preference of MgO(+*) for the attack of primary C-H bonds. This feature represents a notable distinction of the main-group metal oxide MgO(+*) from various transition-metal oxide cations, which show a clear preference for the attack of secondary C-H bonds. The results of complementary theoretical calculations indicate that the C-H bond activation of larger alkanes by the MgO(+*) cation is subject to pronounced kinetic control.