Analysis of Minerals as Electrode Materials for Ca-based Rechargeable Batteries.

Rechargeable lithium-ion batteries dominate the consumer electronics and electric vehicle markets. However, concerns on Li availability have prompted the development of alternative high energy density electrochemical energy storage systems. Rechargeable batteries based on a Ca metal anode can exhibit advantages in terms of energy density, safety and cost. The development of rechargeable Ca metal batteries requires the identification of suitable high specific energy cathode materials. This work focuses on Ca-bearing minerals because they represent stable and abundant compounds. Suitable minerals should contain a transition metal able of being reversibly reduced and oxidized, which points to several major classes of silicates and carbonates: olivine (CaFeSiO4; kirschsteinite), pyroxene (CaFe/MnSi2O6; hedenbergite and johannsenite, respectively), garnet (Ca3Fe/Cr2Si3O12; andradite and uvarovite, respectively), amphibole (Ca2Fe5Si8O22(OH)2; ferroactinolite) and double carbonates (CaMn(CO3)2; kutnahorite and CaFe(CO3)2; ankerite). This work discusses their electrode characteristics based on crystal chemistry analysis and density functional theory (DFT) calculations. The results indicate that upon Ca deintercalation, compounds such as pyroxene, garnet and double carbonate minerals could display high theoretical energy densities (ranging from 780 to 1500 Wh/kg) with moderate structural modifications. As a downside, DFT calculations indicate a hampered Ca mobility in their crystal structures. The overall analysis then disregards olivine, garnet, pyroxene, amphibole and double carbonates as structural types for future Ca-cathode materials design.

Tuning the local solvent composition at a drug carrier surface: the effect of dimethyl sulfoxide/water mixture on the photofunctional properties of hypericin-ß-lactoglobulin complexes.

Aggregation is a major problem for the anti-microbial photodynamic applications of hydrophobic photosensitizers since it strongly reduces the amount of singlet oxygen generated in aqueous solutions. Binding of hypericin (Hyp) to the milk whey protein ß-lactoglobulin (ßLG), occurring at the two hydrophobic cavities located at the interface of the protein homodimer, can be exploited to confer water-solubility and biocompatibility to the photosensitizer. The introduction of a small amount of the organic cosolvent dimethyl sulfoxide (DMSO) leads to a remarkable improvement of the photophysical properties of the complex Hyp-ßLG by increasing its fluorescence emission and singlet oxygen photosensitization quantum yields. Surprisingly, the ability of the complex to photo-inactivate bacteria of the strain Staphylococcus aureus is strongly reduced in the presence of DMSO, despite the higher yield of photosensitization. The reasons for this apparently contradictory behavior are investigated, providing new insights into the use of carrier systems for hydrophobic photosensitizers.

Structural Plasticity in Globins: Role of Protein Dynamics in Defining Ligand Migration Pathways.

Globins are a family of proteins characterized by the presence of the heme prosthetic group and involved in variety of biological functions in the cell. Due to their biological relevance and widespread distribution in all kingdoms of life, intense research efforts have been devoted to disclosing the relationships between structural features, protein dynamics, and function. Particular attention has been paid to the impact of differences in amino acid sequence on the topological features of docking sites and cavities and to the influence of conformational flexibility in facilitating the migration of small ligands through these cavities. Often, tunnels are carved in the interior of globins, and ligand exchange is regulated by gating residues. Understanding the subtle intricacies that relate the differences in sequence with the structural and dynamical features of globins with the ultimate aim of rationalizing the thermodynamics and kinetics of ligand binding continues to be a major challenge in the field. Due to the evolution of computational techniques, significant advances into our understanding of these questions have been made. In this review we focus our attention on the analysis of the ligand migration pathways as well as the function of the structural cavities and tunnels in a series of representative globins, emphasizing the synergy between experimental and theoretical approaches to gain a comprehensive knowledge into the molecular mechanisms of this diverse family of proteins.

Development and validation of hydrophobic molecular fields derived from the quantum mechanical IEF/PCM-MST solvation models in 3D-QSAR.

Since the development of structure-activity relationships about 50 years ago, 3D-QSAR methods belong to the most refined ligand-based in silico techniques for prediction of biological data using physicochemical molecular fields. In this scenario, this study reports the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized MST continuum solvation model to be used in 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. To this end, five sets of compounds reported in the literature (dopamine D2/D4 antagonists, antifungal 2-aryl-4-chromanones, and inhibitors of GSK-3, cruzain and thermolysin) have been revisited. The results derived from the QM/MST-based hydrophobic descriptors have been compared with previous CoMFA and CoMSIA studies, and examined in light of the available X-ray crystallographic structures of the targets. The analysis reveals that the combination of electrostatic and nonelectrostatic components of the octanol/water partition coefficient yields pharmacophoric models fully comparable with the predictive potential of standard 3D-QSAR techniques. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the introduction of the QM/MST-based descriptors, which could be easily adapted to other continuum solvation formalisms, paves the way to novel computational strategies for disclosing structure-activity relationships in drug design. © 2016 Wiley Periodicals, Inc.

Water resources management in southern Europe: clues for a research and innovation based regional hypercluster.

European countries are facing increasing pressures on their water resources despite stringent regulations and systematic efforts on environmental protection. In this context, research and innovation play a strategic role reinforcing the efficiency of water policies. The present study provides a multilevel assessment of research and innovation practices in the field of water resource management in southern European countries and regions (more specifically; Cyprus, Albania, Poitou-Charentes in France, Andalusia in Spain and the North of Portugal). The analysis was based on a strategic framework aimed at gaining an insight of the current constraints, as well as of the existing and future technological solutions for a better water resource management. The triple helix model proved to be a useful analytical framework for assessing the efforts of different groups towards a common goal. The analysis proved the existence of a significant evolution in the use of technological tools to assist decision-making processes in integrated river basin management in all regions. Nevertheless, the absence of formal channels for knowledge and data exchange between researchers and water resource managers complicates the formers involvement in the decision-making process regarding water allocation. Both researchers and consultants emphasize the low availability of data, together with the need to advance on water resource economics as relevant constraints in the field. The SWOT analysis showed similar concerns among the participating regions and provided a battery of effective projects that resulted in the preparation of a Joint Action Plan.

High pressure reveals structural determinants for globin hexacoordination: neuroglobin and myoglobin cases.

The influence of pressure on the equilibrium between five-(5c) and six-coordination (6c) forms in neuroglobin (Ngb) and myoglobin (Mb) has been examined by means of molecular dynamics (MD) simulations at normal and high pressure. The results show that the main effect of high pressure is to reduce the protein mobility without altering the structure in a significant manner. Moreover, our data suggest that the equilibrium between 5c and 6c states in globins is largely controlled by the structure and dynamics of the C-D region. Finally, in agreement with the available experimental data, the free energy profiles obtained from steered MD for both proteins indicate that high pressure enhances hexacoordination. In Ngb, the shift in equilibrium is mainly related to an increase in the 6c-->5c transition barrier, whereas in Mb such a shift is primarily due to a destabilization of the 5c state.

Targets and tools: recent advances in the development of anti-HCV nucleic acids.

Hepatitis C virus (HCV), the major etiological agent of transfusion-associated non-A, non-B hepatitis, is a severe health problem affecting up to 3% of the world population. Since its identification in 1989, enormous efforts have been made to characterize the viral cycle. However, many details regarding the virus' penetration of hepatocytes, its replication and translation, and the assembling of virions remain unknown, mostly because of a lack of an efficient culture system. This has also hampered the development of fully effective antiviral drugs. Current treatments based on the combination of interferon and ribavirin trigger a sustained virological response in only 40% of infected individuals, thus the development of alternative therapeutic strategies is a major research goal. Nucleic acid based therapeutic agents may be of some potential in hepatitis C treatment. In recent years, much effort has gone into the improvement of DNA and RNA molecules as specific gene silencing tools. This review summarizes the state of the art in the development of new HCV therapies, paying special attention to those involving antisense oligonucleotides, aptamers, ribozymes, decoys and siRNA inhibitors. The identification of potential viral targets is also discussed.

Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE.

A new series of donepezil-tacrine hybrid related derivatives have been synthesised as dual acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. These new hybrids combined a tacrine, 6-chlorotacrine or acridine unit as catalytic binding site and indanone (the heterocycle present in donepezil) or phthalimide moiety as peripheral binding site of the enzyme, connected through a different linker tether length. One of the synthesised compounds emerged as a potent and selective AChE inhibitor, which is able to displace propidium in a competition assay. These results seem to confirm the ability of this inhibitor to bind simultaneously to both sites of the enzyme and make it a promising lead for developing disease-modifying drugs for the future treatment of Alzheimer's disease. To gain insight into the molecular determinants that modulate the inhibitory activity of these compounds, a molecular modelling study was performed to explore their binding to the enzyme.

Rational design of reversible acetylcholinesterase inhibitors.

A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors.

Ligand-induced changes in the binding sites of proteins.

Classical molecular interaction potentials, in conjunction with other theoretical techniques, are used to analyze the dependence of the binding sites of representative proteins on the bound ligand. It is found that the ligand bound introduces in general small structural perturbations at the binding site of the protein. However, such small structural changes can lead to important alterations in the recognition pattern of the protein. The impact of these findings in docking procedures is discussed.

3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 A resolution: kinetic and molecular dynamic correlates.

Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.

Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors.

Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (+/-)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.

Classical molecular interaction potentials: improved setup procedure in molecular dynamics simulations of proteins.

The latest version of the classical molecular interaction potential (CMIP) has the ability to predict the position of crystallographic waters in several proteins with great accuracy. This article analyzes the ability of the CMIP functional to improve the setup procedure of the molecular system in molecular dynamics (MD) simulations of proteins. To this end, the CMIP strategy is used to include both water molecules and counterions in different protein systems. The structural details of the configurations sampled from trajectories obtained using the CMIP setup procedure are compared with those obtained from trajectories derived from a standard equilibration process. The results show that standard MD simulations can lead to artifactual results, which are avoided using the CMIP setup procedure. Because the CMIP is easy to implement at a low computational cost, it can be very useful in obtaining reliable MD trajectories.

Theoretical studies of d(A:T)-based parallel-stranded DNA duplexes.

Poly d(A:T) parallel-stranded DNA duplexes based on the Hoogsteen and reverse Watson-Crick hydrogen bond pairing are studied by means of extensive molecular dynamics (MD) simulations and molecular mechanics coupled to Poisson-Boltzmann (MM-PB/SA) calculations. The structural, flexibility, and reactivity characteristics of Hoogsteen and reverse Watson-Crick parallel duplexes are described from the analysis of the trajectories. Theoretical calculations show that the two parallel duplexes are less stable than the antiparallel Watson-Crick duplex. The difference in stability between antiparallel and parallel duplexes increases steadily as the length of the duplex increases. The reverse Watson-Crick arrangement is slightly more stable than the Hoogsteen duplex, the difference being also increased linearly with the length of the duplex. A subtle balance of intramolecular and solvation terms is responsible for the preference of a given helical structure.

Parallel-stranded hairpins containing 8-aminopurines. Novel efficient probes for triple-helix formation.

We describe novel oligomers with a greater propensity to form triplexes than oligomers containing only natural bases. They consist of a polypyrimidine sequence linked head-to-head with a polypurine sequence carrying one or several 8-aminoadenine or 8-aminoguanines. The presence of 8-aminopurines also stabilised the parallel-stranded duplex structure.

The effect of amino groups on the stability of DNA duplexes and triplexes based on purines derived from inosine.

The effect of amino groups attached at positions 2 and 8 of the hypoxanthine moiety in the structure, reactivity and stability of DNA duplexes and triplexes is studied by means of quantum mechanical calculations, as well as extended molecular dynamics (MD) and thermodynamic integration (MD/TI) simulations. Theoretical estimates of the change in stability related to 2'-deoxyguanosine (G) --> 2'-deoxyinosine (I) --> 8-amino-2'-deoxyinosine (8AI) mutations have been experimentally verified, after synthesis of the corresponding compounds. An amino group placed at position 2 stabilizes the duplex, as expected, and surprisingly also the triplex. The presence of an amino group at position 8 of the hypoxanthine moiety stabilizes the triplex but, surprisingly, destabilizes the duplex. The subtle electronic redistribution occurring upon the introduction of an amino group on the purine seems to be responsible for this surprising behavior. Interesting 'universal base' properties are found for 8AI.

A theoretical investigation on the effect of remote amino groups in hydrogen bonding of nucleic acids.

The effect of remote amino groups in the H-bonding of complementary bases of duplex and triplex DNA has been investigated in the gas phase by means of density functional theory. It is found that amino groups incorporated in regions of the purine that are distant from the H-bonding sites might have a notable influence on the stability of H-bonded dimers. The results show that, in addition to primary and secondary interactions, polarization effects can be relevant for the determination of hydrogen bonding in nucleobases.

Towards improved acetylcholinesterase inhibitors: a structural and computational approach.

During the last years, solving the X-ray crystallographic structure of both the unliganded acetylcholinesterase (AChE) and AChE complexes with various inhibitors has provided valuable knowledge of the interactions that mediate inhibitor binding. This structural information allows us to rationalize differences in binding affinities for related analogues, and more importantly opens new strategies to design compounds with improved pharmacological properties. This is illustrated in the case of the recently reported huprines, which are a new class of very potent and selective acetylcholinesterase inhibitors.

New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease.

Several new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives (tacrine-huperzine A hybrids, huprines) have been synthesized and tested as acetylcholinesterase (AChE) inhibitors. All of the new compounds contain either a methyl or ethyl group at position 9 and one or two (chloro, fluoro, or methyl) substituents at positions 1, 2, or 3. Among the monosubstituted derivatives, the more active are those substituted at position 3, their activity following the order 3-chloro > 3-fluoro > 3-methyl > 3-hydrogen. For the 1,3-difluoro and 1,3-dimethyl derivatives, the effect of the substituents is roughly additive. No significant differences were observed for the inhibitory activity of 9-methyl vs 9-ethyl derivatives mono- or disubstituted at positions 1 and/or 3. The levorotatory enantiomers of these hybrid compounds are much more active (eutomers) than the dextrorotatory forms (distomers) as AChE inhibitors. Compounds rac-20, (-)-20, rac-26, (-)-26, rac-30, (-)-30, and rac-31 showed human AChE inhibitory activities up to 28.5-fold higher than for the corresponding bovine enzyme. Also, rac-19, (-)-20, (-)-30, and rac-31 were very selective for human AChE vs butyrylcholinesterase (BChE), the AChE inhibitory activities being 438-871-fold higher than for BChE. Several hybrid compounds, specially (-)-20 and (-)-30, exhibited tight-binding character, showing higher activity after incubation of the enzyme with the inhibitor than without incubation, though the reversible nature of the enzyme-inhibitor interaction was demonstrated by dialysis. The results of the ex vivo experiments also supported the tight-binding character of compounds (-)-20 and (-)-30 and showed their ability to cross the blood-brain barrier. Molecular modeling simulations of the AChE-inhibitor complex provided a basis to explain the differences in inhibitory activity of these compounds.