Metal–metal bonding in 1st, 2nd and 3rd row transition metal complexes: a topological analysis

A topological analysis based on density functional electronic and spin densities of the bonding characteristics in a series of Fe, Ru, Os, Tc and Rh dimers and trimers bridged, respectively, by μ-1,8-naphthyridine (nap) and μ-2,2′-dipyridylamine (dpa) is presented. By this simple qualitative analysis, we were able to determine the electronic ground state and correlated bonding order for a number of complexes potentially involved in extended metal atom chains (EMAC). Furthermore, we showed in the Ru dimer that it was possible to control the spin state simply by changing the bonded counter-anion.

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Graphical Abstract Electron localization analysis of the bonding properties in [M₂(nap)₄Cl₂]²⁺ and [M₃(dpa)₄(Cl₂] complexes

     

Flavonoid–membrane interactions: Involvement of flavonoid–metal complexes in raft signaling

Flavonoids are polyphenolic compounds produced by plants and delivered to the human body through food. Although the epidemiological analyses of large human populations did not reveal a simple correlation between flavonoid consumption and health, laboratory investigations and clinical trials clearly demonstrate the effectiveness of flavonoids in the prevention of cardiovascular, carcinogenic, neurodegenerative and immune diseases, as well as other diseases. At present, the abilities of flavonoids in the regulation of cell metabolism, gene expression, and protection against oxidative stress are well-known, although certain biophysical aspects of their functioning are not yet clear. Most flavonoids are poorly soluble in water and, similar to lipophilic compounds, have a tendency to accumulate in biological membranes, particularly in lipid rafts, where they can interact with different receptors and signal transducers and influence their functioning through modulation of the lipid-phase behavior. In this study, we discuss the enhancement in the lipophilicity and antioxidative activity of flavonoids after their complexation with transient metal cations. We hypothesize that flavonoid–metal complexes are involved in the formation of molecular assemblies due to the facilitation of membrane adhesion and fusion, protein–protein and protein–membrane binding, and other processes responsible for the regulation of cell metabolism and protection against environmental hazards.     

Metal–bipyridine complexes in DNA backbones and effects on thermal stability

Modified oligonucleotides are showing potential for multiple applications, including drug design, nanoscale building blocks, and biosensors. In an effort to expand the functionality available to DNA, we have placed chelating ligands directly into the backbone of DNA. Between one and three nucleosides were replaced with 2,2′-bipyridine phosphates in 23-mer duplexes of DNA. An array of metal ions were added (Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, and Pt²⁺) and the influences on duplex stability were examined by melting temperature studies. Titrations and UV–vis absorption spectroscopy were used to provide insights into the nature of the metal complexes formed. We found that Ni²⁺ binding to 2,2′-bipyridine typically provided the greatest increase in duplex stability relative to the other metal ions examined. For example, addition of Ni²⁺ to one 2,2′-bipyridine–DNA duplex increased the melting temperature by 13 °C, from 65.0 ± 0.3 to 78.4 ± 0.9 °C. These studies show that metal ions and backbone ligands can be used to regulate DNA structure and stability.     

Analysis of the cytotoxic effects of ruthenium–ketoconazole and ruthenium–clotrimazole complexes on cancer cells

Ruthenium-based compounds have intriguing anti-cancer properties, and some of these novel compounds are currently in clinical trials. To continue the development of new metal-based drug combinations, we coupled ruthenium (Ru) with the azole compounds ketoconazole (KTZ) and clotrimazole (CTZ), which are well-known antifungal agents that also display anticancer properties. We report the activity of a series of 12 Ru–KTZ and Ru–CTZ compounds against three prostate tumor cell lines with different androgen sensitivity, as well as cervical cancer and lymphoblastic lymphoma cell lines. In addition, human cell lines were used to evaluate the toxicity against non-transformed cells and to establish selectivity indexes. Our results indicate that the combination of ruthenium and KTZ/CTZ in a single molecule results in complexes that are more cytotoxic than the individual components alone, displaying in some cases low micromolar CC₅₀ values and high selectivity indexes. Additionally, all compounds are more cytotoxic against prostate cell lines with lower cytotoxicity against non-transformed epidermal cell lines. Some of the compounds were found to primarily induce cell death via apoptosis yet weakly interact with DNA. Our studies also demonstrate that the cytotoxicity induced by our Ru-based compounds is not directly related to their ability to interact with DNA.     

Hydrogen-bonding interactions in adrenaline–water complexes: DFT and QTAIM studies of structures, properties, and topologies

ωB97XD/6-311++G(d,p) calculations were carried out to investigate the hydrogen-bonding interactions between adrenaline (Ad) and water. Six Ad-H(2)O complexes possessing various types of hydrogen bonds (H-bonds) were characterized in terms of their geometries, energies, vibrational frequencies, and electron-density topology. Natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses were performed to elucidate the nature of the hydrogen-bonding interactions in these complexes. The intramolecular H-bond between the amino and carboxyl oxygen atom of Ad was retained in most of the complexes, and cooperativity between the intra- and intermolecular H-bonds was present in some of the complexes. H-bonds in which hydroxyls of Ad/water acted as proton donors were stronger than other H-bonds. Both hydrogen-bonding interactions and structural deformation play important roles in the relative stabilities of the complexes. The intramolecular H-bond was broken during the formation of the most stable complex, which indicates that Ad tends to break the intramolecular H-bond and form two new intermolecular H-bonds with the first water molecule.     

Very strong metal ligand aromatic cation-π interactions in transition metal complexes: intermolecular interaction in tetraphenylborate salts

Strong intermolecular interactions between ligands in cationic metal complexes and aromatic rings of tetraphenylborate anion, so-called metal ligand aromatic cation-π (MLACπ) interactions, were found by screening Cambridge Structural Database. Distances between phenyl ring and ligand are shorter in these structures than in previously reported MLACπ interactions by 0.2 Å.     

Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

Electrospray ionisation mass spectrometry was used to analyse the reactions of metal compounds with mixtures of selected proteins. Three representative medicinally relevant compounds, cisplatin, transplatin and the organometallic ruthenium compound RAPTA-C, were reacted with a pool of three proteins, ubiquitin, cytochrome c and superoxide dismutase, and the reaction products were analysed using high-resolution mass spectrometry. Highly informative electrospray ionisation mass spectra were acquired following careful optimisation of the experimental conditions. The formation of metal–protein adducts was clearly observed for the three proteins. In addition, valuable information was obtained on the nature of the protein-bound metallofragments, on their distribution among the three different proteins and on the binding kinetics. The platinum compounds were less reactive and considerably less selective in protein binding than RAPTA-C, which showed a high affinity towards ubiquitin and cytochrome c, but not superoxide dismutase. In addition, competition studies between cisplatin and RAPTA-C showed that the two metallodrugs have affinities for the same amino acid residues on protein binding. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

General and specific lipid–protein interactions in Na,K-ATPase

The molecular activity of Na,K-ATPase and other P2 ATPases like Ca^2 +-ATPase is influenced by the lipid environment via both general (physical) and specific (chemical) interactions. Whereas the general effects of bilayer structure on membrane protein function are fairly well described and understood, the importance of the specific interactions has only been realized within the last decade due particularly to the growing field of membrane protein crystallization, which has shed new light on the molecular details of specific lipid–protein interactions. It is a remarkable observation that specific lipid–protein interactions seem to be evolutionarily conserved, and conformations of specifically bound lipids at the lipid–protein surface within the membrane are similar in crystal structures determined with different techniques and sources of the protein, despite the rather weak lipid–protein interaction energy. Studies of purified detergent-soluble recombinant αβ or αβFXYD Na,K-ATPase complexes reveal three separate functional effects of phospholipids and cholesterol with characteristic structural selectivity. The observations suggest that these three effects are exerted at separate binding sites for phophatidylserine/cholesterol (stabilizing), polyunsaturated phosphatidylethanolamine (stimulatory), and saturated PC or sphingomyelin/cholesterol (inhibitory), which may be located within three lipid-binding pockets identified in recent crystal structures of Na,K-ATPase. The findings point to a central role of direct and specific interactions of different phospholipids and cholesterol in determining both stability and molecular activity of Na,K-ATPase and possible implications for physiological regulation by membrane lipid composition. This article is part of a special issue titled “Lipid–Protein Interactions.”     

Anion–π interactions in complexes of proteins and halogen-containing amino acids

We analyzed the potential influence of anion–π interactions on the stability of complexes of proteins and halogen-containing non-natural amino acids. Anion–π interactions are distance and orientation dependent and our ab initio calculations showed that their energy can be lower than ?8 kcal mol^?1, while most of their interaction energies lie in the range from ?1 to ?4 kcal mol^?1. About 20 % of these interactions were found to be repulsive. We have observed that Tyr has the highest occurrence among the aromatic residues involved in anion–π interactions, while His made the least contribution. Furthermore, our study showed that 67 % of total interactions in the dataset are multiple anion–π interactions. Most of the amino acid residues involved in anion–π interactions tend to be buried in the solvent-excluded environment. The majority of the anion–π interacting residues are located in regions with helical secondary structure. Analysis of stabilization centers for these complexes showed that all of the six residues capable of anion–π interactions are important in locating one or more of such centers. We found that anion–π interacting residues are sometimes involved in simultaneous interactions with halogens as well. With all that in mind, we can conclude that the anion–π interactions can show significant influence on molecular organization and on the structural stability of the complexes of proteins and halogen-containing non-natural amino acids. Their influence should not be neglected in supramolecular chemistry and crystal engineering fields as well.     

Mutualism and manipulation in Hadza–honeyguide interactions

We investigated the ecology and evolution of interspecific cooperation between the Greater Honeyguide bird, Indicator indicator, and human hunter-gatherers, the Hadza of northern Tanzania. We found that honeyguides increased the Hadza's rate of finding bee nests by 560%, and that the birds led men to significantly higher yielding nests than those found without honeyguides. We estimate that 8–10% of the Hadza's total diet was acquired with the help of honeyguides. Contrary to most depictions of the human-honeyguide relationship, the Hadza did not actively repay honeyguides, but instead, hid, buried, and burned honeycomb, with the intent of keeping the bird hungry and thus more likely to guide again. Such manipulative behavior attests to the importance of social intelligence in hunter-gatherer foraging strategies. We present an evolutionary model for human-honeyguide interactions guided by the behavioral ecology of bees, non-human primates, and hunter-gatherers.     

Vibrio–bivalve interactions in health and disease

In the marine environment, bivalve mollusks constitute habitats for bacteria of the Vibrionaceae family. Vibrios belong to the microbiota of healthy oysters and mussels, which have the ability to concentrate bacteria in their tissues and body fluids, including the hemolymph. Remarkably, these important aquaculture species respond differently to infectious diseases. While oysters are the subject of recurrent mass mortalities at different life stages, mussels appear rather resistant to infections. Thus, Vibrio species are associated with the main diseases affecting the worldwide oyster production. Here, we review the current knowledge on Vibrio–bivalve interaction in oysters (Crassostrea sp.) and mussels (Mytilus sp.). We discuss the transient versus stable associations of vibrios with their bivalve hosts as well as technical issues limiting the monitoring of these bacteria in bivalve health and disease. Based on the current knowledge of oyster/mussel immunity and their interactions with Vibrio species pathogenic for oyster, we discuss how differences in immune effectors could contribute to the higher resistance of mussels to infections. Finally, we review the multiple strategies evolved by pathogenic vibrios to circumvent the potent immune defences of bivalves and how key virulence mechanisms could have been positively or negatively selected in the marine environment through interactions with predators.     

In silico and in vitro studies of transition metal complexes derived from curcumin–isoniazid Schiff base

Abstract

A series of transition metal complexes have been synthesized from biologically active curcumin and isoniazid Schiff base. They are characterized by various spectral techniques like UV–Vis, Fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR) and mass spectroscopies. Moreover, elemental analysis, magnetic susceptibility and molar conductivity measurements are also carried out. All these data evidence that the metal complexes acquire square planar except zinc(II) which adopts a tetrahedral geometry, and they are non-electrolytic in nature. Groove mode of binding between the calf thymus DNA (CT DNA) and metal complexes is confirmed by electronic absorption titration, viscosity and cyclic voltammetry studies. In addition to that, all the metal complexes are able to cleave pUC 19 DNA. Optimized geometry and ground-state electronic structure calculations of all the synthesized compounds are established out by density functional theory (DFT) using B3LYP method which theoretically reveals that copper(II) complex explores higher stability and higher biological accessibility. This is experimentally corroborated by antimicrobial studies. In silico Absorption, Distribution, Metabolism, Excretion (ADME) studies reveal the biological potential of all synthesized complexes, and also biological activity of the ligand is predicted by PASS online biological activity prediction software. Molecular docking studies are also carried out to confirm the groove mode of binding and receptor–complex interactions.     

Tethering,evagination, and vesiculation via cell–cell interactions in microvascular flow

Biomechanics and Modeling in Mechanobiology - Vesiculation is a ubiquitous process undergone by most cell types and serves a variety of vital cell functions; vesiculation from erythrocytes, in...     

Gene–gene and gene–environment interactions in ulcerative colitis

Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene–gene and gene–environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case–Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high-order interactions. Exploratory genotype correlations with UC sub-phenotypes [extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)] were conducted. The combination of 133 UC loci yielded good UC risk predictability [area under the curve (AUC) of 0.86]. A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P = 3.26E?05). Explained UC variance increased from 37 to 42 % after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high-order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene–gene and gene–environment interactions.     

Synthesis,characterization, toxicity,cytogenetic and in vivo antitumor studies of 1,1-dithiolate Cu(II) complexes with di-, tri-, tetra- amines and 1,3-thiazoles. Structure–activity correlation

A series of new mixed-ligand neutral copper(II) complexes of the general type [Cu(amine)(i-MNT)] and [Cu(tz)(i-MNT)] was prepared and characterized by elemental, spectroscopic methods, μ_eff, Λ_μ measurements and molecular modeling studies. The acute toxicity, the cytogenetic and the in vivo antitumor activity of the new complexes, is related to their chemical and physicochemical properties. Among the Cu(II) compounds tested the complex with 2-amino-5-methyl thiazole increases significantly the life span of leukemia P388 bearing mice in vivo.     

Monarch–parasite interactions in managed and roadside prairies

Roadsides cover an extensive area within the United States, are actively managed, and have been considered potential areas of habitat for several taxa. For monarch butterflies (Danaus plexippus), roadsides may act as important habitat along their migration route by providing nectar and host plant resources, which is especially important considering the loss and fragmentation of monarch habitat throughout their breeding range. However, the interactions between monarchs and their parasites may be altered in these areas by management regimes. Monarchs are infected by Ophryocystis elektroscirrha (OE), an obligate, spore-forming protist of monarchs and queens, and Lespesia archippivora, a generalist tachinid fly parasitoid. Roadsides could increase parasitism by concentrating monarchs in certain areas or decrease parasitism by modifying habitat (e.g., the roadside management practice of mowing could reduce the availability of OE spores by removing the above ground portion of host plants and generating re-growth), including the distribution and abundance of host plants. In this study, we compared the proportion of infected monarchs between roadside prairies and managed prairies to evaluate the potential of roadside prairies as habitat for monarch butterflies. Our results suggest that the proportion of infected monarchs does not differ between roadside prairies and managed prairies. Thus, roadsides may provide habitat for monarchs that is similar in quality (at least in terms of parasitism rates) to managed prairies. The role of roadsides as habitat for monarchs should be considered when developing roadside management strategies.     

Integrins and chondrocyte–matrix interactions in articular cartilage

The integrin family of cell adhesion receptors plays a major role in mediating interactions between cells and the extracellular matrix. Normal adult articular chondrocytes express α1β1, α3β1, α5β1, α10β1, αVβ1, αVβ3, and αVβ5 integrins, while chondrocytes from osteoarthritic tissue also express α2β1, α4β1, α6β1. These integrins bind a host of cartilage extracellular matrix (ECM) proteins, most notably fibronectin and collagen types II and VI, which provide signals that regulate cell proliferation, survival, differentiation, and matrix remodeling. By initiating signals in response to mechanical forces, chondrocyte integrins also serve as mechanotransducers. When the cartilage matrix is damaged in osteoarthritis, fragments of fibronectin are generated that signal through the α5β1 integrin to activate a pro-inflammatory and pro-catabolic response which, if left unchecked, could contribute to progressive matrix degradation. The cell signaling pathways activated in response to excessive mechanical signals and to fibronectin fragments are being unraveled and may represent useful therapeutic targets for slowing or stopping progressive matrix destruction in arthritis.