Israel Journal of Chemistry Wiley Online Library : Israel Journal of Chemistryhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2F%28ISSN%291869-5868John Wiley & Sons, Incen© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim0021-21481869-58682017-06-01T00:00:00-05:00June 2017576446559Zinc as an Imaging Biomarker of Prostate Cancerhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700043Zinc as an Imaging Biomarker of Prostate CancerSu-Tang Lo, André F. Martins, Veronica Clavijo Jordan, A. Dean Sherry2017-07-31T03:29:25.842328-05:00doi:10.1002/ijch.201700043John Wiley & Sons, Inc.10.1002/ijch.201700043http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700043Reviewn/an/aAbstract

Zinc has long been the focus of many biological investigations because of its essential role in biology including a catalytic role in many enzymes, a structural role in the many zinc finger proteins, and a physiological role in many secretory cell processes. Divalent zinc is known to be highly abundant in healthy prostate tissues and lower in prostate cancer (PCa). Given the need for newer diagnostic methods for detection of prostate cancer, zinc-responsive probes of various types have been considered as imaging tools for detecting tissue levels of zinc. Among them, recent zinc-responsive MRI probes show great promise for non-invasive detection of zinc ion secretion from the prostate and other tissues in vivo. In this review, we summarize the need for new diagnostic tools and demonstrate how responsive zinc probes and MRI could satisfy this unmet need.

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]]> Zinc has long been the focus of many biological investigations because of its essential role in biology including a catalytic role in many enzymes, a structural role in the many zinc finger proteins, and a physiological role in many secretory cell processes. Divalent zinc is known to be highly abundant in healthy prostate tissues and lower in prostate cancer (PCa). Given the need for newer diagnostic methods for detection of prostate cancer, zinc-responsive probes of various types have been considered as imaging tools for detecting tissue levels of zinc. Among them, recent zinc-responsive MRI probes show great promise for non-invasive detection of zinc ion secretion from the prostate and other tissues in vivo. In this review, we summarize the need for new diagnostic tools and demonstrate how responsive zinc probes and MRI could satisfy this unmet need. Iron Catalyzed Dehydrocoupling of Amine- and Phosphine-Boraneshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700018Iron Catalyzed Dehydrocoupling of Amine- and Phosphine-BoranesNathan T. Coles, Ruth L. Webster2017-07-27T01:25:55.121291-05:00doi:10.1002/ijch.201700018John Wiley & Sons, Inc.10.1002/ijch.201700018http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700018Reviewn/an/aAbstract

Catalytic dehydrocoupling methodologies, whereby dihydrogen is released from a substrate (or intermolecularly from two substrates) is a mild and efficient method to construct main group element-main group element bonds, the products of which can be used in advanced materials, and also for the development of hydrogen storage materials. With growing interest in the potential of compounds such as ammonia-borane to act as hydrogen storage materials which contain a high weight% of H2, along with the current heightened interest in base metal catalyzed processes, this review covers recent developments in amine and phosphine dehydrocoupling catalyzed by iron complexes. The complexes employed, products formed and mechanistic proposals will be discussed.

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]]> Catalytic dehydrocoupling methodologies, whereby dihydrogen is released from a substrate (or intermolecularly from two substrates) is a mild and efficient method to construct main group element-main group element bonds, the products of which can be used in advanced materials, and also for the development of hydrogen storage materials. With growing interest in the potential of compounds such as ammonia-borane to act as hydrogen storage materials which contain a high weight% of H2, along with the current heightened interest in base metal catalyzed processes, this review covers recent developments in amine and phosphine dehydrocoupling catalyzed by iron complexes. The complexes employed, products formed and mechanistic proposals will be discussed. Iron-Catalyzed C−C Bond Formation via Chelation-Assisted C−H Activationhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700047Iron-Catalyzed C−C Bond Formation via Chelation-Assisted C−H ActivationNaohiko Yoshikai2017-07-26T02:15:37.038866-05:00doi:10.1002/ijch.201700047John Wiley & Sons, Inc.10.1002/ijch.201700047http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700047Reviewn/an/aAbstract

This review provides a brief overview of iron-catalyzed C−C bond forming reactions via heteroatom-assisted C−H bond activation, which have been extensively developed in the last decade. Three major types of reactions are discussed, namely, (1) C−H activation/C−C coupling using organometallic reagents under oxidative conditions, (2) C−H activation/C−C coupling using organic electrophiles under redox-neutral conditions, and (3) C−H activation/C−C coupling using unsaturated hydrocarbons under redox-neutral or oxidative conditions.

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]]> This review provides a brief overview of iron-catalyzed C−C bond forming reactions via heteroatom-assisted C−H bond activation, which have been extensively developed in the last decade. Three major types of reactions are discussed, namely, (1) C−H activation/C−C coupling using organometallic reagents under oxidative conditions, (2) C−H activation/C−C coupling using organic electrophiles under redox-neutral conditions, and (3) C−H activation/C−C coupling using unsaturated hydrocarbons under redox-neutral or oxidative conditions. Iron Complexes with Chiral N/P Macrocycles as Catalysts for Asymmetric Transfer Hydrogenationhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700035Iron Complexes with Chiral N/P Macrocycles as Catalysts for Asymmetric Transfer HydrogenationAntonio Mezzetti2017-07-11T02:31:00.223025-05:00doi:10.1002/ijch.201700035John Wiley & Sons, Inc.10.1002/ijch.201700035http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700035Reviewn/an/aAbstract

The present account describes the development of chiral, C2-symmetric N/P macrocyclic ligands that attune to the size and electronic properties of the iron(II) ion to give robust complexes under catalysis conditions. This is not trivial, as the complexes of base metals are substantially less stable than those of precious metals. Also, as these N2P2 macrocycles feature stereogenic P atoms, the control of the stereochemistry at phosphorus is a key synthetic issue. Still, as the macrocyclic effect was insufficient to give robust catalysts under hydrogen transfer conditions, we had to dig deeper into the toolbox of coordination chemistry and use strong-field ancillary ligands other than CO, specifically isonitriles, which additionally offer a further handle to tune the catalyst. The reward was the discovery of the first iron(II) catalyst for the asymmetric transfer hydrogenation of polar double bonds that is highly enantioselective for a broad scope of substrates.

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]]> The present account describes the development of chiral, C2-symmetric N/P macrocyclic ligands that attune to the size and electronic properties of the iron(II) ion to give robust complexes under catalysis conditions. This is not trivial, as the complexes of base metals are substantially less stable than those of precious metals. Also, as these N2P2 macrocycles feature stereogenic P atoms, the control of the stereochemistry at phosphorus is a key synthetic issue. Still, as the macrocyclic effect was insufficient to give robust catalysts under hydrogen transfer conditions, we had to dig deeper into the toolbox of coordination chemistry and use strong-field ancillary ligands other than CO, specifically isonitriles, which additionally offer a further handle to tune the catalyst. The reward was the discovery of the first iron(II) catalyst for the asymmetric transfer hydrogenation of polar double bonds that is highly enantioselective for a broad scope of substrates. Fundamental Developments of Chiral Phase Chromatography in Connection with Enantioselective Synthesis of β-Amino Acidshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700011Fundamental Developments of Chiral Phase Chromatography in Connection with Enantioselective Synthesis of β-Amino AcidsJorge Vargas-Caporali, Eusebio Juaristi2017-07-07T05:41:08.072041-05:00doi:10.1002/ijch.201700011John Wiley & Sons, Inc.10.1002/ijch.201700011http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700011Reviewn/an/aAbstract

A few decades ago, the enantiomeric purities of chiral compounds were usually determined by comparison of experimental optical rotations or by preparation of diastereomeric derivatives followed by analysis of their 1H NMR spectra. This situation changed when Emanuel Gil-Av, Binyamin Feibush and Rosita Charles-Sigler achieved the separation of single enantiomers from racemic α-amino acids by means of a chiral stationary phase. Indeed, chiral chromatography allowed a direct comparison of chromatograms obtained from enantiopure samples with those recorded with their racemates. With the aim of celebrating the relevance of Gil-Av's achievement, this review also presents several applications of chiral chromatography in the area of asymmetric synthesis of β-amino acids.

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]]> A few decades ago, the enantiomeric purities of chiral compounds were usually determined by comparison of experimental optical rotations or by preparation of diastereomeric derivatives followed by analysis of their 1H NMR spectra. This situation changed when Emanuel Gil-Av, Binyamin Feibush and Rosita Charles-Sigler achieved the separation of single enantiomers from racemic α-amino acids by means of a chiral stationary phase. Indeed, chiral chromatography allowed a direct comparison of chromatograms obtained from enantiopure samples with those recorded with their racemates. With the aim of celebrating the relevance of Gil-Av's achievement, this review also presents several applications of chiral chromatography in the area of asymmetric synthesis of β-amino acids. Group 9 Transition Metal-Catalyzed C−H Halogenationshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700053Group 9 Transition Metal-Catalyzed C−H HalogenationsFabian Lied, Tuhin Patra, Frank Glorius2017-07-07T02:15:29.791797-05:00doi:10.1002/ijch.201700053John Wiley & Sons, Inc.10.1002/ijch.201700053http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700053Reviewn/an/aAbstract

The high importance of organic halides as synthetic precursors has led to the development of milder and environmentally benign methods for their synthesis. In this regard, transition metal catalyzed C−H activation has emerged as one of the most promising methods for the synthesis of organic halides with high atom economy and excellent stereo- and regio-control. Despite the dominance of palladium and copper catalysts in the field of C−H halogenation reactions, iridium-, rhodium- and cobalt-complexes have also recently been employed as highly efficient catalysts for the formation of carbon-halogen bonds. This review describes the current state of the art in the field of C−H halogenation reactions using group nine transition metal (Co, Rh, Ir) catalysts.

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]]> The high importance of organic halides as synthetic precursors has led to the development of milder and environmentally benign methods for their synthesis. In this regard, transition metal catalyzed C−H activation has emerged as one of the most promising methods for the synthesis of organic halides with high atom economy and excellent stereo- and regio-control. Despite the dominance of palladium and copper catalysts in the field of C−H halogenation reactions, iridium-, rhodium- and cobalt-complexes have also recently been employed as highly efficient catalysts for the formation of carbon-halogen bonds. This review describes the current state of the art in the field of C−H halogenation reactions using group nine transition metal (Co, Rh, Ir) catalysts. Synthesis and Biological Activity of Octaketides from the Cytosporone Familyhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700023Synthesis and Biological Activity of Octaketides from the Cytosporone FamilyMax von Delius, Christine M. Le, Bernhard Ellinger, Maria Kuzikov, Sheraz Gul, Vy M. Dong2017-07-07T01:45:53.348002-05:00doi:10.1002/ijch.201700023John Wiley & Sons, Inc.10.1002/ijch.201700023http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700023Full Papern/an/aAbstract

Cytosporone B and its simple analogues (e. g., amoitone B) were recently identified as unique agonists for nuclear orphan receptor Nur77. In this study, we have developed an aldehyde C-H activation method for preparing natural and designer analogues from the cytosporone family. In addition, a comprehensive investigation of the compounds’ biological activities and pharmacological liabilities has been conducted and new structure activity relationships (SAR) were derived from the data. Most notably, we found that increased cytotoxicity can be obtained by virtue of fluorine substitution on the hydrophobic acyl chain.

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]]> Cytosporone B and its simple analogues (e. g., amoitone B) were recently identified as unique agonists for nuclear orphan receptor Nur77. In this study, we have developed an aldehyde C-H activation method for preparing natural and designer analogues from the cytosporone family. In addition, a comprehensive investigation of the compounds’ biological activities and pharmacological liabilities has been conducted and new structure activity relationships (SAR) were derived from the data. Most notably, we found that increased cytotoxicity can be obtained by virtue of fluorine substitution on the hydrophobic acyl chain. On Water and its Effect on the Performance of T1-Shortening Contrast Agentshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700037On Water and its Effect on the Performance of T1-Shortening Contrast AgentsKatherine M. Payne, Jennifer M. Wilds, Fabio Carniato, Mauro Botta, Mark Woods2017-07-06T06:35:42.105688-05:00doi:10.1002/ijch.201700037John Wiley & Sons, Inc.10.1002/ijch.201700037http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700037Full Papern/an/aAbstract

The performance of low molecular weight Gd3+ chelates as T1-shortening contrast agents for MRI is limited by their rapid rate of molecular tumbling, which makes them very sensitive to factors that alter the rate of molecular reorientation. Unlike the interactions of these chelates with other solutes present in solution, which have been widely studied, the effect of the solvent water itself on tumbling seems to have been largely ignored. Water has long been known to adopt structures that vary from freely diffusing molecules on one extreme and a more “ice-like” structure on the other. A variety of salts can be used to alter this “structure” of water. Relaxometric studies on inner and outersphere Gd3+ chelates were performed in the presence of both structure making and structure breaking salts. The addition of structure-making salts to low molecular weight Gd3+ chelates was found to increase both the second- and outer-sphere contributions to relaxivity. These results point to a slowing of molecular tumbling arising from an increase solvent structure and therefore microviscosity. The implication of these findings is that the performance of low molecular weight Gd3+ contrast agents is not, as generally assumed, constant in the absence of secondary interactions but may vary depending upon the nature of the solution in which it is dissolved.

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]]> The performance of low molecular weight Gd3+ chelates as T1-shortening contrast agents for MRI is limited by their rapid rate of molecular tumbling, which makes them very sensitive to factors that alter the rate of molecular reorientation. Unlike the interactions of these chelates with other solutes present in solution, which have been widely studied, the effect of the solvent water itself on tumbling seems to have been largely ignored. Water has long been known to adopt structures that vary from freely diffusing molecules on one extreme and a more “ice-like” structure on the other. A variety of salts can be used to alter this “structure” of water. Relaxometric studies on inner and outersphere Gd3+ chelates were performed in the presence of both structure making and structure breaking salts. The addition of structure-making salts to low molecular weight Gd3+ chelates was found to increase both the second- and outer-sphere contributions to relaxivity. These results point to a slowing of molecular tumbling arising from an increase solvent structure and therefore microviscosity. The implication of these findings is that the performance of low molecular weight Gd3+ contrast agents is not, as generally assumed, constant in the absence of secondary interactions but may vary depending upon the nature of the solution in which it is dissolved. Convergent Synthesis of α-Branched Amines by Transition-Metal-Catalyzed C−H Bond Additions to Imineshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700021Convergent Synthesis of α-Branched Amines by Transition-Metal-Catalyzed C−H Bond Additions to IminesJoshua R. Hummel, Jonathan A. Ellman2017-06-29T04:02:08.722219-05:00doi:10.1002/ijch.201700021John Wiley & Sons, Inc.10.1002/ijch.201700021http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700021Reviewn/an/aAbstract

α-Branched amines are ubiquitous in drugs and natural products, and consequently, synthetic methods that provide convergent and efficient entry to these structures are of considerable value. Transition-metal-catalyzed C−H bond additions to imines have the potential to be highly practical and atom-economic approaches for the synthesis of a diverse and complex array of α-branched amine products. These strategies typically employ readily available starting inputs, display high functional group compatibility, and often avoid the production of stoichiometric waste byproducts. A number of C−H functionalization methods have also been developed that incorporate cascade cyclization pathways to give amine-substituted carbocycles, and in many cases, proceed with the formation of multiple stereogenic centers. Advances in the area of asymmetric C−H bond additions to imines have also been achieved through the use of chiral imine N-substituents as well as by enantioselective catalysis.

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]]> α-Branched amines are ubiquitous in drugs and natural products, and consequently, synthetic methods that provide convergent and efficient entry to these structures are of considerable value. Transition-metal-catalyzed C−H bond additions to imines have the potential to be highly practical and atom-economic approaches for the synthesis of a diverse and complex array of α-branched amine products. These strategies typically employ readily available starting inputs, display high functional group compatibility, and often avoid the production of stoichiometric waste byproducts. A number of C−H functionalization methods have also been developed that incorporate cascade cyclization pathways to give amine-substituted carbocycles, and in many cases, proceed with the formation of multiple stereogenic centers. Advances in the area of asymmetric C−H bond additions to imines have also been achieved through the use of chiral imine N-substituents as well as by enantioselective catalysis. MRI-based Sensors for In Vivo Imaging of Metal Ions in Biologyhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700016MRI-based Sensors for In Vivo Imaging of Metal Ions in BiologyHyla Allouche-Arnon, Nishanth D. Tirukoti, Amnon Bar-Shir2017-06-29T01:35:35.842766-05:00doi:10.1002/ijch.201700016John Wiley & Sons, Inc.10.1002/ijch.201700016http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700016Reviewn/an/aAbstract

Although much is known about the diverse roles of metal ions in biology, most of the acquired knowledge was obtained with fluorescent dyes or electrophysiological approaches. However, the ability to non-invasively monitor variation in metal ions and to assess their physiological distribution in health and disease is very limited. Recent advances in the field of molecular magnetic resonance imaging (MRI) have offered new capabilities through the design and development of MRI-responsive sensors for a wide range of applications, including the ability to sense and spatially map metal ions. Here, we briefly summarize the recent progress in the development and performance of MRI sensors designed to monitor metal ions in biology while emphasizing their in vivo uses, their limitations, and remaining challenges. Among the proposed MRI-sensors, Zn2+ and Ca2+ responsive agents are those that have already been used in live intact subjects, and therefore, these will be emphasized here.

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]]> Although much is known about the diverse roles of metal ions in biology, most of the acquired knowledge was obtained with fluorescent dyes or electrophysiological approaches. However, the ability to non-invasively monitor variation in metal ions and to assess their physiological distribution in health and disease is very limited. Recent advances in the field of molecular magnetic resonance imaging (MRI) have offered new capabilities through the design and development of MRI-responsive sensors for a wide range of applications, including the ability to sense and spatially map metal ions. Here, we briefly summarize the recent progress in the development and performance of MRI sensors designed to monitor metal ions in biology while emphasizing their in vivo uses, their limitations, and remaining challenges. Among the proposed MRI-sensors, Zn2+ and Ca2+ responsive agents are those that have already been used in live intact subjects, and therefore, these will be emphasized here. Developing High Field MRI Contrast Agents by Tuning the Rotational Dynamics: Bisaqua GdAAZTA-based Dendrimershttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700041Developing High Field MRI Contrast Agents by Tuning the Rotational Dynamics: Bisaqua GdAAZTA-based DendrimersLorenzo Tei, Giuseppe Gugliotta, Giuseppe Gambino, Marianna Fekete, Mauro Botta2017-06-26T07:07:40.917112-05:00doi:10.1002/ijch.201700041John Wiley & Sons, Inc.10.1002/ijch.201700041http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700041Full Papern/an/aAbstract

Monomeric and dimeric AAZTA-based bifunctional chelators (AAZTA=6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid) were attached to different generations (G0, G1 and G2) of ethylenediamine-cored PAMAM dendrimers (PAMAM=polyamidoamine) to obtain a series of six dendrimeric systems with 4 to 32 chelates at the periphery. These GdIII-loaded dendrimers have molecular weight ranging from 3.5 to 25 kDa, thus allowing a systematic investigation on the changes in relaxivity (r1) with the variation of the rotational dynamics following the increase in molecular size. Variable-temperature 17O NMR (on the dimeric building block Gd2L2) and 1H Nuclear Magnetic Relaxation Dispersion measurements at different temperatures indicate that the water exchange lifetime (τM∼90 ns) of the two inner sphere water molecules does not represent a limiting factor to the relaxivity of the systems. The r1 values at 1.5 T (60 MHz) and 298 K increases from 10.2 mM−1 s−1 for the monomer GdL1 to 31.4 mM−1 s−1 for the dendrimer Gd32G2-32 (+308 %). However, the relaxivity (per Gd) does not show a linear dependence on the molecular mass, but rather the enhancement tends to attenuate markedly for larger systems. This effect has been attributed to the growing decrease in correlation between local rotational motions and global molecular tumbling.

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]]> Monomeric and dimeric AAZTA-based bifunctional chelators (AAZTA=6-amino-6-methylperhydro-1,4-diazepine tetraacetic acid) were attached to different generations (G0, G1 and G2) of ethylenediamine-cored PAMAM dendrimers (PAMAM=polyamidoamine) to obtain a series of six dendrimeric systems with 4 to 32 chelates at the periphery. These GdIII-loaded dendrimers have molecular weight ranging from 3.5 to 25 kDa, thus allowing a systematic investigation on the changes in relaxivity (r1) with the variation of the rotational dynamics following the increase in molecular size. Variable-temperature 17O NMR (on the dimeric building block Gd2L2) and 1H Nuclear Magnetic Relaxation Dispersion measurements at different temperatures indicate that the water exchange lifetime (τM∼90 ns) of the two inner sphere water molecules does not represent a limiting factor to the relaxivity of the systems. The r1 values at 1.5 T (60 MHz) and 298 K increases from 10.2 mM−1 s−1 for the monomer GdL1 to 31.4 mM−1 s−1 for the dendrimer Gd32G2-32 (+308 %). However, the relaxivity (per Gd) does not show a linear dependence on the molecular mass, but rather the enhancement tends to attenuate markedly for larger systems. This effect has been attributed to the growing decrease in correlation between local rotational motions and global molecular tumbling. Special Issue: Amyloid Aggregationhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700052Special Issue: Amyloid AggregationYifat Miller, John Straub2017-06-21T02:08:17.356038-05:00doi:10.1002/ijch.201700052John Wiley & Sons, Inc.10.1002/ijch.201700052http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700052Editorialn/an/aParaHydrogen Hyperpolarized Substrates for Molecular Imaging Studieshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700030ParaHydrogen Hyperpolarized Substrates for Molecular Imaging StudiesEleonora Cavallari, Carla Carrera, Francesca Reineri2017-06-20T02:28:25.004796-05:00doi:10.1002/ijch.201700030John Wiley & Sons, Inc.10.1002/ijch.201700030http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700030Reviewn/an/aAbstract

Parahydrogen induced polarization (PHIP) is a chemistry based, cheap and easy to handle hyperpolarization method that allows to increase the sensitivity of magnetic resonance signals of several orders of magnitude. This powerful tool has not coalesced in the field of biomedical studies due to the lack of suitable hyperpolarization substrates, of commercial parahydrogen polarizers and to the presence of metal complex in the solutions of products. Here is reported an overview of the recent advances in these fields, with particular attention to the issues that have been tackled in order to allow the translation of parahydrogen based hyperpolarization methods into a widely applicable molecular imaging tool for biomedical research.

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]]> Parahydrogen induced polarization (PHIP) is a chemistry based, cheap and easy to handle hyperpolarization method that allows to increase the sensitivity of magnetic resonance signals of several orders of magnitude. This powerful tool has not coalesced in the field of biomedical studies due to the lack of suitable hyperpolarization substrates, of commercial parahydrogen polarizers and to the presence of metal complex in the solutions of products. Here is reported an overview of the recent advances in these fields, with particular attention to the issues that have been tackled in order to allow the translation of parahydrogen based hyperpolarization methods into a widely applicable molecular imaging tool for biomedical research. Recent Advances in Bifunctional Paramagnetic Chelates for MRIhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700028Recent Advances in Bifunctional Paramagnetic Chelates for MRIGiovanni B. Giovenzana, Luciano Lattuada, Roberto Negri2017-06-14T08:40:21.764863-05:00doi:10.1002/ijch.201700028John Wiley & Sons, Inc.10.1002/ijch.201700028http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700028Reviewn/an/aAbstract

Magnetic resonance imaging (MRI) is a non-invasive diagnostic modality routinely employed in modern clinical medicine to collect images of the internal organs of the human body. Contrast agents (CA) are usually administered to patients to improve the sensitivity of this technique and nowadays these agents are gadolinium complexes. Bifunctional chelating agents (BFCAs) are dual molecules containing a multidentate ligand, able to strongly coordinate a metal ion, and a reactive moiety for conjugation purposes. With BFCAs an easy labelling of biomolecules or vectors with paramagnetic ions is possible, allowing the in vivo MRI visualization of diseases at cellular or molecular level.

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]]> Magnetic resonance imaging (MRI) is a non-invasive diagnostic modality routinely employed in modern clinical medicine to collect images of the internal organs of the human body. Contrast agents (CA) are usually administered to patients to improve the sensitivity of this technique and nowadays these agents are gadolinium complexes. Bifunctional chelating agents (BFCAs) are dual molecules containing a multidentate ligand, able to strongly coordinate a metal ion, and a reactive moiety for conjugation purposes. With BFCAs an easy labelling of biomolecules or vectors with paramagnetic ions is possible, allowing the in vivo MRI visualization of diseases at cellular or molecular level. Unexpected Solvent Effects in the Isomerization of iPrPCPIr(η2-PhC≡CPh) to a 1-Iridaindenehttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700013Unexpected Solvent Effects in the Isomerization of iPrPCPIr(η2-PhC≡CPh) to a 1-IridaindeneMiles Wilklow-Marnell, William W. Brennessel, William D. Jones2017-06-14T06:21:10.531114-05:00doi:10.1002/ijch.201700013John Wiley & Sons, Inc.10.1002/ijch.201700013http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700013Full Papern/an/aAbstract

The reaction of iPrPCPIr with diphenylacetylene (iPrPCP=κ3-2,6-C6H3(CH2P(iPr)2)2), generated by dehydrogenation of iPrPCPIrH4 with tert-butylethylene, readily provides the π-adduct iPrPCPIr(η2-PhC≡CPh) in quantitative yield at room temperature. Heating solutions of iPrPCPIr(η2-PhC≡CPh) in aromatic hydrocarbon solvents leads to isomerization forming the 1-iridaindene iPrPCPIr(C8H5(2-Ph)). Surprisingly, this seemingly intramolecular reaction presents a kinetic isotope effect of 4.6 in C6H6 versus C6D6 solvent. The rate of this isomerization is effected by the availability of easily activated C−H bonds (i. e. aromatic C(sp2)-H without ortho-substituents), and is strongly dependent upon the ratio of C−H to C−D bonds. Experiments indicate that many, or all, of the steps in this process may be reversible and that a highly fluxional C−H/D addition product is present during isomerization.

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]]> The reaction of iPrPCPIr with diphenylacetylene (iPrPCP=κ3-2,6-C6H3(CH2P(iPr)2)2), generated by dehydrogenation of iPrPCPIrH4 with tert-butylethylene, readily provides the π-adduct iPrPCPIr(η2-PhC≡CPh) in quantitative yield at room temperature. Heating solutions of iPrPCPIr(η2-PhC≡CPh) in aromatic hydrocarbon solvents leads to isomerization forming the 1-iridaindene iPrPCPIr(C8H5(2-Ph)). Surprisingly, this seemingly intramolecular reaction presents a kinetic isotope effect of 4.6 in C6H6 versus C6D6 solvent. The rate of this isomerization is effected by the availability of easily activated C−H bonds (i. e. aromatic C(sp2)-H without ortho-substituents), and is strongly dependent upon the ratio of C−H to C−D bonds. Experiments indicate that many, or all, of the steps in this process may be reversible and that a highly fluxional C−H/D addition product is present during isomerization. Importance of DOTA derivatives in bimodal imaginghttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700024Importance of DOTA derivatives in bimodal imagingSatya Narayana Murthy Chilla, Céline Henoumont, Luce Vander Elst, Robert N. Muller, Sophie Laurent2017-06-13T08:25:36.346646-05:00doi:10.1002/ijch.201700024John Wiley & Sons, Inc.10.1002/ijch.201700024http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700024Reviewn/an/aAbstract

The clinical applications of multimodal probes are numerous since a few decades. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has played an important role in diagnostic and therapeutic areas. The vast applications of DOTA as chelator have been explored in magnetic resonance imaging (MRI) and in radioisotope chemistry. Moreover, the possibility to functionalize the macrocycle with pendant arms has allowed to explore new functionalities as bimodal imaging agents. Different combinations are possible between the different possible imaging techniques like Magnetic Resonance Imaging, Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Optical imaging (OI). The main use of DOTA and its derivatives was for MRI as gadolinium complexes. It was then further extended to the complexation with europium or terbium for optical imaging. Although other chelates are available such as DTPA or NOTA, derivatives of DOTA were often the primary choice due to their versatility. DOTA derivatives can indeed also be complexed with radioisotopes and conjugated to peptides which leads to targeted contrast agents for PET or SPECT. Depending on the chosen imaging modality, a variety of radiometals can be complexed with DOTA, e.i. 64Cu and 68Ga for PET, or 111In and 90Y for SPECT. Conjugation of chromophores to gadolinium complexes of DOTA derivatives can also lead to bimodal agents for MRI and OI. In this review, we will provide the applications of DOTA and its derivatives in different imaging modalities and their clinical applications.

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]]> The clinical applications of multimodal probes are numerous since a few decades. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has played an important role in diagnostic and therapeutic areas. The vast applications of DOTA as chelator have been explored in magnetic resonance imaging (MRI) and in radioisotope chemistry. Moreover, the possibility to functionalize the macrocycle with pendant arms has allowed to explore new functionalities as bimodal imaging agents. Different combinations are possible between the different possible imaging techniques like Magnetic Resonance Imaging, Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Optical imaging (OI). The main use of DOTA and its derivatives was for MRI as gadolinium complexes. It was then further extended to the complexation with europium or terbium for optical imaging. Although other chelates are available such as DTPA or NOTA, derivatives of DOTA were often the primary choice due to their versatility. DOTA derivatives can indeed also be complexed with radioisotopes and conjugated to peptides which leads to targeted contrast agents for PET or SPECT. Depending on the chosen imaging modality, a variety of radiometals can be complexed with DOTA, e.i. 64Cu and 68Ga for PET, or 111In and 90Y for SPECT. Conjugation of chromophores to gadolinium complexes of DOTA derivatives can also lead to bimodal agents for MRI and OI. In this review, we will provide the applications of DOTA and its derivatives in different imaging modalities and their clinical applications. Progress toward quantitative in vivo chemical exchange saturation transfer (CEST) MRIhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700025Progress toward quantitative in vivo chemical exchange saturation transfer (CEST) MRIYang Ji, Iris Yuwen Zhou, Bensheng Qiu, Phillip Zhe Sun2017-06-13T08:20:23.894654-05:00doi:10.1002/ijch.201700025John Wiley & Sons, Inc.10.1002/ijch.201700025http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700025Reviewn/an/aAbstract

Chemical exchange saturation transfer (CEST) MRI provides a sensitive detection mechanism for imaging dilute labile protons, complementing the routine radiological exams. Enormous progress has been achieved in CEST MRI and image analysis, from the mathematical modeling, CEST agent design, and most importantly, increasing adoption of CEST imaging in the clinical setting. Therefore, CEST imaging represents an emerging field that involves multiple disciplines and together made a remarkable transition from the simplistic CEST-weighted MRI to quantitative CEST (qCEST) analysis. This review focuses on the recent advancements in CEST quantification techniques and findings of in vivo CEST imaging in representative disorders of ischemia, tumor, and epilepsy. In addition, limitations of current CEST methodologies are examined that should help guide future development of more sensitive and quantitative CEST imaging techniques and ultimately, facilitate their adoption in the clinical setting.

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]]> Chemical exchange saturation transfer (CEST) MRI provides a sensitive detection mechanism for imaging dilute labile protons, complementing the routine radiological exams. Enormous progress has been achieved in CEST MRI and image analysis, from the mathematical modeling, CEST agent design, and most importantly, increasing adoption of CEST imaging in the clinical setting. Therefore, CEST imaging represents an emerging field that involves multiple disciplines and together made a remarkable transition from the simplistic CEST-weighted MRI to quantitative CEST (qCEST) analysis. This review focuses on the recent advancements in CEST quantification techniques and findings of in vivo CEST imaging in representative disorders of ischemia, tumor, and epilepsy. In addition, limitations of current CEST methodologies are examined that should help guide future development of more sensitive and quantitative CEST imaging techniques and ultimately, facilitate their adoption in the clinical setting. Imaging of Extracellular pH Using Hyperpolarized Moleculeshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700017Imaging of Extracellular pH Using Hyperpolarized MoleculesChristian Hundshammer, Stephan Düwel, Franz Schilling2017-06-12T08:45:31.934994-05:00doi:10.1002/ijch.201700017John Wiley & Sons, Inc.10.1002/ijch.201700017http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700017Reviewn/an/aAbstract

Many diseases can overrule natural pH regulatory mechanisms and alter the extracellular pH (pHe). A non-invasive method that resolves pHe in vivo with high spatial and temporal resolution could therefore improve diagnosis and monitoring of diseases, contributing to the concept of precision medicine. During the last decades, several techniques have been proposed to image pHe non-invasively. The majority of these methods rely on magnetic resonance because of its good spatial resolution, high penetration depth, non-ionizing radiation and excellent complimentary soft tissue contrast. Dissolution dynamic nuclear polarization (DNP) is an emerging concept to enhance nuclear magnetic resonance (NMR) signals by more than four orders of magnitude, making it possible to observe in vivo metabolic processes in real-time. Here, we summarize and review recent developments in pHe imaging techniques based on hyperpolarization methods and give an overview of recently discovered hyperpolarized pH sensor molecules that have been applied in vitro and in vivo.

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]]> Many diseases can overrule natural pH regulatory mechanisms and alter the extracellular pH (pHe). A non-invasive method that resolves pHe in vivo with high spatial and temporal resolution could therefore improve diagnosis and monitoring of diseases, contributing to the concept of precision medicine. During the last decades, several techniques have been proposed to image pHe non-invasively. The majority of these methods rely on magnetic resonance because of its good spatial resolution, high penetration depth, non-ionizing radiation and excellent complimentary soft tissue contrast. Dissolution dynamic nuclear polarization (DNP) is an emerging concept to enhance nuclear magnetic resonance (NMR) signals by more than four orders of magnitude, making it possible to observe in vivo metabolic processes in real-time. Here, we summarize and review recent developments in pHe imaging techniques based on hyperpolarization methods and give an overview of recently discovered hyperpolarized pH sensor molecules that have been applied in vitro and in vivo. Self-assembled Protein Fibril-metal Oxide Nanocompositeshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600118Self-assembled Protein Fibril-metal Oxide NanocompositesA. Levin, T. O. Mason, T. P. J. Knowles, U. Shimanovich2017-05-24T09:00:24.270321-05:00doi:10.1002/ijch.201600118John Wiley & Sons, Inc.10.1002/ijch.201600118http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600118Communicationn/an/aAbstract

Protein aggregation is commonly associated with the onset and development of neurodegenerative disorders, including Alzheimer's, Parkinson's and other forms of pathological disorders. While this phenomenon has historically been studied in the context of its relevance to human health, over the past decade significant research effort has focused on utilizing amyloid-like protein assemblies as building blocks for the development of functional biomaterials and a number of protein-based functional materials have been demonstrated. Here we extend this concept by synthesizing hybrid organic/inorganic microcapsules containing metal-based NPs and protein nanofibrils as a nanocomposite. To this effect, we exploit the propensity of lysozyme to self-assemble into amyloid nanofibrils and their functionalization by carboxyl-modified Fe3O4 NPs. We use a microfluidics-based approach to control the micron scale moprhology of the newly formed nanocomposites. Our results illustrate the potential ofthis strategy as a platform for fabricating microcapsules from nanofibril-inorganic NPs hybrid materials.

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]]> Protein aggregation is commonly associated with the onset and development of neurodegenerative disorders, including Alzheimer's, Parkinson's and other forms of pathological disorders. While this phenomenon has historically been studied in the context of its relevance to human health, over the past decade significant research effort has focused on utilizing amyloid-like protein assemblies as building blocks for the development of functional biomaterials and a number of protein-based functional materials have been demonstrated. Here we extend this concept by synthesizing hybrid organic/inorganic microcapsules containing metal-based NPs and protein nanofibrils as a nanocomposite. To this effect, we exploit the propensity of lysozyme to self-assemble into amyloid nanofibrils and their functionalization by carboxyl-modified Fe3O4 NPs. We use a microfluidics-based approach to control the micron scale moprhology of the newly formed nanocomposites. Our results illustrate the potential ofthis strategy as a platform for fabricating microcapsules from nanofibril-inorganic NPs hybrid materials. Flexible N-Termini of Amyloid β-Protein Oligomers: A Link between Structure and Activity?http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600097Flexible N-Termini of Amyloid β-Protein Oligomers: A Link between Structure and Activity?Brigita Urbanc2017-02-03T02:56:21.362871-05:00doi:10.1002/ijch.201600097John Wiley & Sons, Inc.10.1002/ijch.201600097http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600097Reviewn/an/aAbstract

Revised amyloid cascade hypothesis of Alzheimer′s disease (AD) states that amyloid β-protein (Aβ) triggers the disease through formation of soluble low molecular weight (LMW) assemblies, called oligomers, which are challenging to characterize experimentally as well as computationally due to their heterogeneous and polymorphic nature, lack of ordered structure, and short lifetimes. Recent findings challenge the view of Aβ oligomers as exclusively toxic entities by revealing their dual, protective and disruptive nature in the context of immune response and AD, respectively. In this review, the understanding of Aβ oligomer formation and structure is discussed from the AD perspective. The structure-activity relationship (SAR) that implicates flexible, solvent exposed N-termini of Aβ oligomers, observed in computer simulations, in mediating their toxic as well as protective activity is proposed.

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]]> Revised amyloid cascade hypothesis of Alzheimer′s disease (AD) states that amyloid β-protein (Aβ) triggers the disease through formation of soluble low molecular weight (LMW) assemblies, called oligomers, which are challenging to characterize experimentally as well as computationally due to their heterogeneous and polymorphic nature, lack of ordered structure, and short lifetimes. Recent findings challenge the view of Aβ oligomers as exclusively toxic entities by revealing their dual, protective and disruptive nature in the context of immune response and AD, respectively. In this review, the understanding of Aβ oligomer formation and structure is discussed from the AD perspective. The structure-activity relationship (SAR) that implicates flexible, solvent exposed N-termini of Aβ oligomers, observed in computer simulations, in mediating their toxic as well as protective activity is proposed. Theory of Amyloid Fibril Nucleation from Folded Proteinshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600079Theory of Amyloid Fibril Nucleation from Folded ProteinsLingyun Zhang, Jeremy D. Schmit2017-01-30T08:55:32.121333-05:00doi:10.1002/ijch.201600079John Wiley & Sons, Inc.10.1002/ijch.201600079http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600079Full Papern/an/aAbstract

We present a theoretical model for the nucleation of amyloid fibrils. In our model, we use helix-coil theory to describe the equilibrium between a soluble native state and an aggregation-prone unfolded state. We then extend the theory to include oligomers with β-sheet cores, and calculate the free energy of these states using estimates for the energies of H-bonds, steric-zipper interactions, and the conformational entropy cost of forming secondary structure. We find that states with fewer than ∼10 β-strands are unstable, relative to the dissociated state, and three β-strands is the highest free-energy state. We then use a modified version of classical nucleation theory to compute the nucleation rate of fibrils from a supersaturated solution of monomers, dimers, and trimers. The nucleation rate has a nonmonotonic dependence on denaturant concentration, reflecting the competing effects of destabilizing the fibril and increasing the concentration of unfolded monomers. We estimate heterogeneous nucleation rates, and discuss the application of our model to secondary nucleation.

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]]> We present a theoretical model for the nucleation of amyloid fibrils. In our model, we use helix-coil theory to describe the equilibrium between a soluble native state and an aggregation-prone unfolded state. We then extend the theory to include oligomers with β-sheet cores, and calculate the free energy of these states using estimates for the energies of H-bonds, steric-zipper interactions, and the conformational entropy cost of forming secondary structure. We find that states with fewer than ∼10 β-strands are unstable, relative to the dissociated state, and three β-strands is the highest free-energy state. We then use a modified version of classical nucleation theory to compute the nucleation rate of fibrils from a supersaturated solution of monomers, dimers, and trimers. The nucleation rate has a nonmonotonic dependence on denaturant concentration, reflecting the competing effects of destabilizing the fibril and increasing the concentration of unfolded monomers. We estimate heterogeneous nucleation rates, and discuss the application of our model to secondary nucleation. Conformational Transitions of the Amyloid-β Peptide Upon Copper(II) Binding and pH Changeshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600108Conformational Transitions of the Amyloid-β Peptide Upon Copper(II) Binding and pH ChangesQinghua Liao, Michael C. Owen, Olujide O. Olubiyi, Bogdan Barz, Birgit Strodel2017-01-20T06:11:24.307148-05:00doi:10.1002/ijch.201600108John Wiley & Sons, Inc.10.1002/ijch.201600108http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600108Full Papern/an/aAbstract

Amyloid-β (Aβ) is a natively unfolded peptide found in all Alzheimer's disease patients as the major component of fibrillar plaques, which are recognized as an important pathological hallmark in Alzheimer's disease. The binding of copper to Aβ increases its neurotoxicity, as Cu2+ causes Aβ to become redox active and decreases the lag time associated with Aβ aggregation. In addition, the pH is a major factor that influences both the Aβ aggregation rates and Cu2+ binding. Hamiltonian replica exchange molecular dynamics (H-REMD) simulations enable atomistic insights into the effects of pH and Cu2+ complexation on the structure and dynamics of Aβ. To study the Aβ1–42/Cu2+ complex, we have developed new force-field parameters for the divalent copper ion ligated by the two histidine residues, His6 and His13, as well as the amine and carbonyl groups of Asp1, in a distorted square-planar geometry. Our comparative simulations reveal that both Cu2+ binding and a low pH-mimicking acidosis, linked to inflammatory processes in vivo, accelerate the formation of β-strands in Aβ1–42 and lead to the stabilization of salt bridges, previously shown to promote Aβ aggregation. The results suggest that Cu2+ binding and mild acidic conditions can shift the conformational equilibrium towards aggregation-prone conformers for the monomeric Aβ.

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]]> Amyloid-β (Aβ) is a natively unfolded peptide found in all Alzheimer's disease patients as the major component of fibrillar plaques, which are recognized as an important pathological hallmark in Alzheimer's disease. The binding of copper to Aβ increases its neurotoxicity, as Cu2+ causes Aβ to become redox active and decreases the lag time associated with Aβ aggregation. In addition, the pH is a major factor that influences both the Aβ aggregation rates and Cu2+ binding. Hamiltonian replica exchange molecular dynamics (H-REMD) simulations enable atomistic insights into the effects of pH and Cu2+ complexation on the structure and dynamics of Aβ. To study the Aβ1–42/Cu2+ complex, we have developed new force-field parameters for the divalent copper ion ligated by the two histidine residues, His6 and His13, as well as the amine and carbonyl groups of Asp1, in a distorted square-planar geometry. Our comparative simulations reveal that both Cu2+ binding and a low pH-mimicking acidosis, linked to inflammatory processes in vivo, accelerate the formation of β-strands in Aβ1–42 and lead to the stabilization of salt bridges, previously shown to promote Aβ aggregation. The results suggest that Cu2+ binding and mild acidic conditions can shift the conformational equilibrium towards aggregation-prone conformers for the monomeric Aβ. Reversing the Amyloid Trend: Mechanism of Fibril Assembly and Dissolution of the Repeat Domain from a Human Functional Amyloidhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600080Reversing the Amyloid Trend: Mechanism of Fibril Assembly and Dissolution of the Repeat Domain from a Human Functional AmyloidRyan P. McGlinchey, Jennifer C. Lee2017-01-19T10:06:01.880347-05:00doi:10.1002/ijch.201600080John Wiley & Sons, Inc.10.1002/ijch.201600080http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600080Reviewn/an/aAbstract

Amyloids are traditionally observed in the context of disease. However, there is growing momentum that these structures can serve a beneficial role where the amyloid carries out a specific function. These so called ‘functional amyloids’ have all the structural hallmarks of disease-associated amyloids, raising the question as to what differentiates a well-behaved benign amyloid from a lethally destructive one. Here, we review our work on the repeat domain (RPT) from Pmel17, an important functional amyloid involved in melanin biosynthesis. Particularly, we focused our attention on the unique reversible aggregation-disaggregation process of RPT that is controlled strictly by solution pH. This pH dependence of RPT amyloid formation functions as a switch to control fibril assembly and maintains the benign nature that is associated with functional amyloids.

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]]> Amyloids are traditionally observed in the context of disease. However, there is growing momentum that these structures can serve a beneficial role where the amyloid carries out a specific function. These so called ‘functional amyloids’ have all the structural hallmarks of disease-associated amyloids, raising the question as to what differentiates a well-behaved benign amyloid from a lethally destructive one. Here, we review our work on the repeat domain (RPT) from Pmel17, an important functional amyloid involved in melanin biosynthesis. Particularly, we focused our attention on the unique reversible aggregation-disaggregation process of RPT that is controlled strictly by solution pH. This pH dependence of RPT amyloid formation functions as a switch to control fibril assembly and maintains the benign nature that is associated with functional amyloids. Cerebrospinal Fluid Proteins as Regulators of Beta-amyloid Aggregation and Toxicityhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600078Cerebrospinal Fluid Proteins as Regulators of Beta-amyloid Aggregation and ToxicityKayla M. Pate, Regina M. Murphy2017-01-18T03:40:29.17027-05:00doi:10.1002/ijch.201600078John Wiley & Sons, Inc.10.1002/ijch.201600078http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600078Reviewn/an/aAbstract

Amyloid disorders, such as Alzheimer's, are almost invariably late-onset diseases. One defining diagnostic feature of Alzheimer's disease is the deposition of beta-amyloid as extracellular plaques, primarily in the hippocampus. This raises the question: are there natural protective agents that prevent beta-amyloid from depositing, and is it loss of this protection that leads to onset of disease? Proteins in cerebrospinal fluid (CSF) have been suggested to act as just such natural protective agents. Here, we describe some of the early evidence that led to this suggestion, and we discuss, in greater detail, two CSF proteins that have garnered the bulk of the attention.

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]]> Amyloid disorders, such as Alzheimer's, are almost invariably late-onset diseases. One defining diagnostic feature of Alzheimer's disease is the deposition of beta-amyloid as extracellular plaques, primarily in the hippocampus. This raises the question: are there natural protective agents that prevent beta-amyloid from depositing, and is it loss of this protection that leads to onset of disease? Proteins in cerebrospinal fluid (CSF) have been suggested to act as just such natural protective agents. Here, we describe some of the early evidence that led to this suggestion, and we discuss, in greater detail, two CSF proteins that have garnered the bulk of the attention. α-Synuclein Oligomers: A Study in Diversityhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600116α-Synuclein Oligomers: A Study in DiversityFemke van Diggelen, Armand W. J. W. Tepper, Mihaela M. Apetri, Daniel E. Otzen2016-12-29T09:00:33.660796-05:00doi:10.1002/ijch.201600116John Wiley & Sons, Inc.10.1002/ijch.201600116http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600116Reviewn/an/aAbstract

A critical step in Parkinson's disease (PD) is the formation of toxic α-synuclein oligomers (αSOs). In vitro αSOs are formed by self-assembly of α-synuclein at high concentrations, or by the addition of, for example, dopamine, lipids, ethanol, or metal ions. These αSOs are structurally distinct from the unfolded monomer and aggregated β-sheet fibrils. Nevertheless, the literature reports a wide variety of αSO shapes, sizes, and proposed toxic mechanisms. This heterogeneous character makes it difficult to form a unifying picture. Here, we present an overview of the different αSO species made in vitro, providing a tool for better comparison of different protocols and the ensuing αSOs, and emphasizing the striking versatility in the appearance and properties of these critical species. We also summarize what is known of the biological activities of different αSOs. Despite a large and increasing level of insight into αSO effects in vitro, we still lack strong insight into the structures and sizes of αSO species formed in vivo. Once this is established, it may be possible to generate more uniform protocols that could stimulate further efforts to develop viable PD biomarker assays and therapies.

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]]> A critical step in Parkinson's disease (PD) is the formation of toxic α-synuclein oligomers (αSOs). In vitro αSOs are formed by self-assembly of α-synuclein at high concentrations, or by the addition of, for example, dopamine, lipids, ethanol, or metal ions. These αSOs are structurally distinct from the unfolded monomer and aggregated β-sheet fibrils. Nevertheless, the literature reports a wide variety of αSO shapes, sizes, and proposed toxic mechanisms. This heterogeneous character makes it difficult to form a unifying picture. Here, we present an overview of the different αSO species made in vitro, providing a tool for better comparison of different protocols and the ensuing αSOs, and emphasizing the striking versatility in the appearance and properties of these critical species. We also summarize what is known of the biological activities of different αSOs. Despite a large and increasing level of insight into αSO effects in vitro, we still lack strong insight into the structures and sizes of αSO species formed in vivo. Once this is established, it may be possible to generate more uniform protocols that could stimulate further efforts to develop viable PD biomarker assays and therapies. The Amyloid-β Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ionshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600105The Amyloid-β Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal IonsCecilia Wallin, Jinghui Luo, Jüri Jarvet, Sebastian K. T. S. Wärmländer, Astrid Gräslund2016-12-28T08:36:09.594261-05:00doi:10.1002/ijch.201600105John Wiley & Sons, Inc.10.1002/ijch.201600105http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600105Reviewn/an/aAbstract

This review describes interactions between the amyloid-β peptide (Aβ) involved in Alzheimer's disease (AD) and endogenous metal ions and proteins, with an emphasis on future potential drug therapies and targets. AD is characterised by loss of neurons, memory, and cognitive functions, and by formation of cerebral senile plaque deposits. These plaques consist mainly of aggregated Aβ peptides. AD pathology includes a) on the molecular level imbalanced concentrations of Aβ peptides and metal ions, and formation of amyloid structures, and b) on the physiological level a combination of inflammatory responses and oxidative stress effects causing neuronal death. Interestingly, certain blood proteins and metal ions can affect the Aβ amyloid aggregation process. These interactions are the topics of the present review. A deeper understanding of these interactions could facilitate new therapeutic strategies against AD. Previous therapeutic approaches and trials are also briefly described.

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]]> This review describes interactions between the amyloid-β peptide (Aβ) involved in Alzheimer's disease (AD) and endogenous metal ions and proteins, with an emphasis on future potential drug therapies and targets. AD is characterised by loss of neurons, memory, and cognitive functions, and by formation of cerebral senile plaque deposits. These plaques consist mainly of aggregated Aβ peptides. AD pathology includes a) on the molecular level imbalanced concentrations of Aβ peptides and metal ions, and formation of amyloid structures, and b) on the physiological level a combination of inflammatory responses and oxidative stress effects causing neuronal death. Interestingly, certain blood proteins and metal ions can affect the Aβ amyloid aggregation process. These interactions are the topics of the present review. A deeper understanding of these interactions could facilitate new therapeutic strategies against AD. Previous therapeutic approaches and trials are also briefly described. Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears?http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600081Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears?Rehana Akter, Andisheh Abedini, Zachary Ridgway, Xiaoxue Zhang, Joel Kleinberg, Ann Marie Schmidt, Daniel P. Raleigh2016-12-19T08:15:56.266614-05:00doi:10.1002/ijch.201600081John Wiley & Sons, Inc.10.1002/ijch.201600081http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600081Full Papern/an/aAbstract

Much of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid-rich diet without deleterious metabolic consequences. In contrast, transgenic rodents expressing the human neuropancreatic polypeptide hormone amylin develop hyperglycemia and extensive pancreatic islet amyloid when fed a high-fat diet. The process of islet amyloid formation by human amylin contributes to β-cell dysfunction and loss of β-cell mass in type 2 diabetes. We show that ursine amylin is considerably less amyloidogenic and less toxic to β-cells than human amylin, consistent with the hypothesis that part of the adaptation of bears to metabolic challenges might include protection from islet amyloidosis-induced β-cell toxicity. Ursine and human amylin differ at four locations: H18R, S20G, F23L, and S29P. These are interesting from a biophysical perspective, since the S20G mutation accelerates amyloid formation, but the H18R slows it. An H18RS20G double mutant of human amylin behaves similarly to the H18R mutant, indicating that the substitution at position 18 dominates the S20G replacement. These data suggest one possible mechanism underpinning the protection of bears against metabolic challenges and provide insight into the design of soluble analogs of human amylin.

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]]> Much of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid-rich diet without deleterious metabolic consequences. In contrast, transgenic rodents expressing the human neuropancreatic polypeptide hormone amylin develop hyperglycemia and extensive pancreatic islet amyloid when fed a high-fat diet. The process of islet amyloid formation by human amylin contributes to β-cell dysfunction and loss of β-cell mass in type 2 diabetes. We show that ursine amylin is considerably less amyloidogenic and less toxic to β-cells than human amylin, consistent with the hypothesis that part of the adaptation of bears to metabolic challenges might include protection from islet amyloidosis-induced β-cell toxicity. Ursine and human amylin differ at four locations: H18R, S20G, F23L, and S29P. These are interesting from a biophysical perspective, since the S20G mutation accelerates amyloid formation, but the H18R slows it. An H18RS20G double mutant of human amylin behaves similarly to the H18R mutant, indicating that the substitution at position 18 dominates the S20G replacement. These data suggest one possible mechanism underpinning the protection of bears against metabolic challenges and provide insight into the design of soluble analogs of human amylin. Fluorescent Markers for Amyloid-β Detection: Computational Insightshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600114Fluorescent Markers for Amyloid-β Detection: Computational InsightsFrancesca Peccati, Stefano Pantaleone, Xavier Solans-Monfort, Mariona Sodupe2016-12-01T09:11:36.190346-05:00doi:10.1002/ijch.201600114John Wiley & Sons, Inc.10.1002/ijch.201600114http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600114Reviewn/an/aAbstract

In vivo detection of cerebral amyloid-β plaques is essential for an early diagnosis of Alzheimer′s disease. Optical imaging, which employs fluorescent markers emitting in the near-infrared range, is a growing alternative to nuclear techniques, with indisputable advantages. The rational design of amyloid markers requires optimization of both the optical and binding properties, and of their mutual interaction. In this work, the structural aspects that determine the performance of selected amyloid markers have been analyzed, focusing on the contributions offered by computational techniques.

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]]> In vivo detection of cerebral amyloid-β plaques is essential for an early diagnosis of Alzheimer′s disease. Optical imaging, which employs fluorescent markers emitting in the near-infrared range, is a growing alternative to nuclear techniques, with indisputable advantages. The rational design of amyloid markers requires optimization of both the optical and binding properties, and of their mutual interaction. In this work, the structural aspects that determine the performance of selected amyloid markers have been analyzed, focusing on the contributions offered by computational techniques. Generation of Amyloid-β Peptides by γ-Secretasehttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600073Generation of Amyloid-β Peptides by γ-SecretaseRodrigo Aguayo-Ortiz, Laura Dominguez2016-11-25T05:21:17.026248-05:00doi:10.1002/ijch.201600073John Wiley & Sons, Inc.10.1002/ijch.201600073http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600073Reviewn/an/aAbstract

γ-Secretase is a four-component membrane-embedded aspartyl protease involved in the final cleavage step of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. Different amino-acid lengths of Aβ peptide can be produced by this enzyme, of which the oligomerization and aberrant accumulation of the product containing 42 amino acids (Aβ42) has been associated with the development and formation of amyloid-β plaques in the brain of Alzheimer's disease (AD) patients. Herein, we review some of the most important topics associated with the structure and activity of γ-secretase and the factors that alter the substrate cleavage pattern, critical to the formation of the different isoforms of the amyloid-β peptides.

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]]> γ-Secretase is a four-component membrane-embedded aspartyl protease involved in the final cleavage step of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. Different amino-acid lengths of Aβ peptide can be produced by this enzyme, of which the oligomerization and aberrant accumulation of the product containing 42 amino acids (Aβ42) has been associated with the development and formation of amyloid-β plaques in the brain of Alzheimer's disease (AD) patients. Herein, we review some of the most important topics associated with the structure and activity of γ-secretase and the factors that alter the substrate cleavage pattern, critical to the formation of the different isoforms of the amyloid-β peptides. Formation of Apoptosis-Inducing Amyloid Fibrils by Tryptophanhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600076Formation of Apoptosis-Inducing Amyloid Fibrils by TryptophanShira Shaham-Niv, Pavel Rehak, Lela Vuković, Lihi Adler-Abramovich, Petr Král, Ehud Gazit2016-11-16T04:47:01.417197-05:00doi:10.1002/ijch.201600076John Wiley & Sons, Inc.10.1002/ijch.201600076http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600076Full Papern/an/aAbstract

Many major degenerative disorders are associated with the formation of amyloid fibrils by proteins and peptides. Recent studies have extended the repertoire of amyloidogenic building blocks to non-proteinaceous entities, including amino acids and nucleobases. Here, based on the high propensity of tryptophan-containing proteins and peptides to form amyloid fibrils, we explored the self-assembly profile of this amino acid. We discovered that tryptophan forms fibrillary assemblies with a diameter of 15–75 nm. These fibrils bind the thioflavin T amyloid-specific dye and show a typical spectrum of amyloid proteins upon binding. Furthermore, the assemblies show significant cytotoxicity triggered by an apoptosis mechanism, similar to that known for amyloids. As a control, the non-amyloidogenic amino acid alanine was used under the same conditions and did not show any toxicity. Molecular dynamics simulations were used to explore the possible growth mechanism, molecular organization, and stability of tryptophan amyloidal fibrils. Taken together, we provide further extension to the amyloid hypothesis and additional indication for a knwon mechanism of toxicity for both amyloid-associated and metabolic disorders.

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]]> Many major degenerative disorders are associated with the formation of amyloid fibrils by proteins and peptides. Recent studies have extended the repertoire of amyloidogenic building blocks to non-proteinaceous entities, including amino acids and nucleobases. Here, based on the high propensity of tryptophan-containing proteins and peptides to form amyloid fibrils, we explored the self-assembly profile of this amino acid. We discovered that tryptophan forms fibrillary assemblies with a diameter of 15–75 nm. These fibrils bind the thioflavin T amyloid-specific dye and show a typical spectrum of amyloid proteins upon binding. Furthermore, the assemblies show significant cytotoxicity triggered by an apoptosis mechanism, similar to that known for amyloids. As a control, the non-amyloidogenic amino acid alanine was used under the same conditions and did not show any toxicity. Molecular dynamics simulations were used to explore the possible growth mechanism, molecular organization, and stability of tryptophan amyloidal fibrils. Taken together, we provide further extension to the amyloid hypothesis and additional indication for a knwon mechanism of toxicity for both amyloid-associated and metabolic disorders. Molecular Simulations of Amyloid Structures, Toxicity, and Inhibitionhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600075Molecular Simulations of Amyloid Structures, Toxicity, and InhibitionMingzhen Zhang, Baiping Ren, Hong Chen, Yan Sun, Jie Ma, Binbo Jiang, Jie Zheng2016-11-16T03:17:28.343948-05:00doi:10.1002/ijch.201600075John Wiley & Sons, Inc.10.1002/ijch.201600075http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600075Reviewn/an/aAbstract

The misfolding and aggregation of proteins and peptides into amyloid fibrils are believed to be responsible for the dysfunction and death of neuron cells in many neurodegenerative diseases. Resolving the atomic structures of amyloid peptides at different aggregation stages by molecular simulations has opened new ways to probe the molecular mechanisms of amyloid aggregation, toxicity, and inhibition, as well as to validate computational data with available experimental ones. In this review article, we summarize some recent and important findings on: 1) a number of atomic structures of amyloid oligomers with typical β-sheet-rich conformations, related to amyloid aggregation; 2) different amyloid peptide-induced membrane-disruption mechanisms, related to amyloid toxicity; and 3) rational design of different amyloid inhibitors capable of preventing amyloid aggregation and toxicity, related to amyloid inhibition. All these findings will provide some mechanistic implications for molecular mechanisms of amyloid aggregation, toxicity, and inhibition, which are fundamentally and practically important for the treatment of amyloid diseases.

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]]> The misfolding and aggregation of proteins and peptides into amyloid fibrils are believed to be responsible for the dysfunction and death of neuron cells in many neurodegenerative diseases. Resolving the atomic structures of amyloid peptides at different aggregation stages by molecular simulations has opened new ways to probe the molecular mechanisms of amyloid aggregation, toxicity, and inhibition, as well as to validate computational data with available experimental ones. In this review article, we summarize some recent and important findings on: 1) a number of atomic structures of amyloid oligomers with typical β-sheet-rich conformations, related to amyloid aggregation; 2) different amyloid peptide-induced membrane-disruption mechanisms, related to amyloid toxicity; and 3) rational design of different amyloid inhibitors capable of preventing amyloid aggregation and toxicity, related to amyloid inhibition. All these findings will provide some mechanistic implications for molecular mechanisms of amyloid aggregation, toxicity, and inhibition, which are fundamentally and practically important for the treatment of amyloid diseases. Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregationhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600096Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid AggregationKian Kamgar-Parsi, James Tolchard, Birgit Habenstein, Antoine Loquet, Akira Naito, Ayyalusamy Ramamoorthy2016-11-15T08:27:23.247913-05:00doi:10.1002/ijch.201600096John Wiley & Sons, Inc.10.1002/ijch.201600096http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600096Reviewn/an/aAbstract

Under appropriate conditions, peptides and proteins can assemble from their native state into prefibrillar oligomers and then mature into fibrillar aggregates. This transition forms the molecular basis of several pathologies, often related to the deposition of these amyloid fibrils. Several hormone peptides involved in fundamental biological processes have the tendency to self-assemble into amyloid fibrils, resulting in a loss of their native functions, and more importantly, entailing devastating consequences, such as the formation of amyloid depositions. Calcitonin is a 32 amino-acid hormone peptide that can be considered a molecular paradigm for the central events associated with hormone misfolding. Calcitonin in its native form is involved in various physiological functions, including mediating calcium homeostasis and maintaining bone structure. It is the latter function that has motivated the use of calcitonin as an aqueous therapeutic agent for the treatment of bone-related pathologies such as osteoporosis and Paget's disease. Despite some success as a therapeutic, calcitonin's ability to control these diseases is limited by its aggregation along the canonical amyloid aggregation pathway, compromising its long-term stability as a therapeutic agent. A better understanding of the misfolding process would not only provide the structural basis to improve calcitonin's long-term stability and activity as a therapeutic, but also provide valuable insights into pathological aggregation of other amyloids. In this work, we review the physiological roles of calcitonin, its structure, and aggregation process, and consider the effects of calcitonin's structure on its role as a therapeutic.

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]]> Under appropriate conditions, peptides and proteins can assemble from their native state into prefibrillar oligomers and then mature into fibrillar aggregates. This transition forms the molecular basis of several pathologies, often related to the deposition of these amyloid fibrils. Several hormone peptides involved in fundamental biological processes have the tendency to self-assemble into amyloid fibrils, resulting in a loss of their native functions, and more importantly, entailing devastating consequences, such as the formation of amyloid depositions. Calcitonin is a 32 amino-acid hormone peptide that can be considered a molecular paradigm for the central events associated with hormone misfolding. Calcitonin in its native form is involved in various physiological functions, including mediating calcium homeostasis and maintaining bone structure. It is the latter function that has motivated the use of calcitonin as an aqueous therapeutic agent for the treatment of bone-related pathologies such as osteoporosis and Paget's disease. Despite some success as a therapeutic, calcitonin's ability to control these diseases is limited by its aggregation along the canonical amyloid aggregation pathway, compromising its long-term stability as a therapeutic agent. A better understanding of the misfolding process would not only provide the structural basis to improve calcitonin's long-term stability and activity as a therapeutic, but also provide valuable insights into pathological aggregation of other amyloids. In this work, we review the physiological roles of calcitonin, its structure, and aggregation process, and consider the effects of calcitonin's structure on its role as a therapeutic. Membrane Binding of Parkinson's Protein α-Synuclein: Effect of Phosphorylation at Positions 87 and 129 by the S to D Mutation Approachhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600083Membrane Binding of Parkinson's Protein α-Synuclein: Effect of Phosphorylation at Positions 87 and 129 by the S to D Mutation ApproachPravin Kumar, Nathalie Schilderink, Vinod Subramaniam, Martina Huber2016-11-10T08:00:27.13762-05:00doi:10.1002/ijch.201600083John Wiley & Sons, Inc.10.1002/ijch.201600083http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600083Full Papern/an/aAbstract

Human α-synuclein, a protein relevant in the brain with so-far unknown function, plays an important role in Parkinson's disease. The phosphorylation state of αS was related to the disease, prompting interest in this process. The presumed physiological function and the disease action of αS involves membrane interaction. Here, we study the effect of phosphorylation at positions 87 and 129, mimicked by the mutations S87A, S129A (nonphosphorylated) and S87D, S129D (phosphorylated) on membrane binding. Local binding is detected by spin-label continuous-wave electron paramagnetic resonance. For S87A/D, six positions (27, 56, 63, 69, 76, and 90) are probed; and for S129A/D, three (27, 56, and 69). Binding to large unilamellar vesicles of 100 nm diameter of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine in a 1 : 1 composition is not affected by the phosphorylation state of S129. For phosphorylation at S87, local unbinding of αS from the membrane is observed. We speculate that modulating the local membrane affinity by phosphorylation could tune the way αS interacts with different membranes; for example, tuning its membrane fusion activity.

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]]> Human α-synuclein, a protein relevant in the brain with so-far unknown function, plays an important role in Parkinson's disease. The phosphorylation state of αS was related to the disease, prompting interest in this process. The presumed physiological function and the disease action of αS involves membrane interaction. Here, we study the effect of phosphorylation at positions 87 and 129, mimicked by the mutations S87A, S129A (nonphosphorylated) and S87D, S129D (phosphorylated) on membrane binding. Local binding is detected by spin-label continuous-wave electron paramagnetic resonance. For S87A/D, six positions (27, 56, 63, 69, 76, and 90) are probed; and for S129A/D, three (27, 56, and 69). Binding to large unilamellar vesicles of 100 nm diameter of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine in a 1 : 1 composition is not affected by the phosphorylation state of S129. For phosphorylation at S87, local unbinding of αS from the membrane is observed. We speculate that modulating the local membrane affinity by phosphorylation could tune the way αS interacts with different membranes; for example, tuning its membrane fusion activity. Oligomer Formation and Cross-Seeding: The New Frontierhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600103Oligomer Formation and Cross-Seeding: The New FrontierKathleen Farmer, Julia E. Gerson, Rakez Kayed2016-10-28T08:25:43.61413-05:00doi:10.1002/ijch.201600103John Wiley & Sons, Inc.10.1002/ijch.201600103http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600103Reviewn/an/aAbstract

The accumulation of protein aggregates in the brain is a defining feature of a number of neurodegenerative diseases. Though diseases vary in the composition of aggregated proteins (amyloid-β and tau are primarily implicated in Alzheimer's disease, α-synuclein is the primary protein aggregate in Parkinson's disease, etc.), similarities in the formation of soluble intermediate aggregates, some of which go on to deposit in stable fibrillar structures, suggests that the protein sequence may be far less important than the aggregate conformation to toxicity and onset of disease. Growing evidence suggests that intermediate or independently formed oligomeric aggregates are more highly toxic than fibrils, and are more efficient seeds for the aggregation of endogenous protein. Furthermore, the overlap of different aggregated proteins in disease, as well as the ability of amyloid oligomers to cross-seed the aggregation of each other, suggests that synergistic interactions between varying aggregant proteins is a critical component in neurodegeneration. The progression of aggregates along defined pathways throughout the brain is crucial to the spread of disease and likely depends upon the transport of aggregates from affected to unaffected brain regions. Thus, the presence of oligomeric seeds that more efficiently seed the aggregation of homologous and diverse proteins may underlie neurodegeneration.

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]]> The accumulation of protein aggregates in the brain is a defining feature of a number of neurodegenerative diseases. Though diseases vary in the composition of aggregated proteins (amyloid-β and tau are primarily implicated in Alzheimer's disease, α-synuclein is the primary protein aggregate in Parkinson's disease, etc.), similarities in the formation of soluble intermediate aggregates, some of which go on to deposit in stable fibrillar structures, suggests that the protein sequence may be far less important than the aggregate conformation to toxicity and onset of disease. Growing evidence suggests that intermediate or independently formed oligomeric aggregates are more highly toxic than fibrils, and are more efficient seeds for the aggregation of endogenous protein. Furthermore, the overlap of different aggregated proteins in disease, as well as the ability of amyloid oligomers to cross-seed the aggregation of each other, suggests that synergistic interactions between varying aggregant proteins is a critical component in neurodegeneration. The progression of aggregates along defined pathways throughout the brain is crucial to the spread of disease and likely depends upon the transport of aggregates from affected to unaffected brain regions. Thus, the presence of oligomeric seeds that more efficiently seed the aggregation of homologous and diverse proteins may underlie neurodegeneration. Compilation and Analysis of Enzymes, Engineered Antibodies, and Nanoparticles Designed to Interfere with Amyloid-β Aggregationhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600093Compilation and Analysis of Enzymes, Engineered Antibodies, and Nanoparticles Designed to Interfere with Amyloid-β AggregationJun Zhao, Buyong Ma, Ruth Nussinov2016-10-25T03:35:36.50947-05:00doi:10.1002/ijch.201600093John Wiley & Sons, Inc.10.1002/ijch.201600093http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600093Reviewn/an/aAbstract

The abnormal accumulation and aggregation of amyloid β (Aβ) is one of the key factors of the synaptic impairment in Alzheimer's disease. Biomolecules, e.g., apolipoproteins, and membrane receptors, are implicated in the aggregation and toxicity of Aβ. Engineered molecules, such as enzymes, antibodies, and nanoparticles, are designed to interfere with these processes. We compile structural information on these molecules and their essential roles in the complex processes of aggregation, disaggregation, degradation, clearance, and inhibition of Aβ. The interactions between Aβ and its partners have no obvious emerging commonalities. One exception is the recognition of the N-terminal region of Aβ peptides by antibody heavy and light chains, which are facilitated by cooperative interaction not observed in other Aβ-peptide molecules. Overall, the emerging picture charts a diverse, to date unexplored, landscape and serves as the first-of-its-kind partner- and scenario-specific analysis.

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]]> The abnormal accumulation and aggregation of amyloid β (Aβ) is one of the key factors of the synaptic impairment in Alzheimer's disease. Biomolecules, e.g., apolipoproteins, and membrane receptors, are implicated in the aggregation and toxicity of Aβ. Engineered molecules, such as enzymes, antibodies, and nanoparticles, are designed to interfere with these processes. We compile structural information on these molecules and their essential roles in the complex processes of aggregation, disaggregation, degradation, clearance, and inhibition of Aβ. The interactions between Aβ and its partners have no obvious emerging commonalities. One exception is the recognition of the N-terminal region of Aβ peptides by antibody heavy and light chains, which are facilitated by cooperative interaction not observed in other Aβ-peptide molecules. Overall, the emerging picture charts a diverse, to date unexplored, landscape and serves as the first-of-its-kind partner- and scenario-specific analysis. Coarse-grained and All-atom Simulations towards the Early and Late Steps of Amyloid Fibril Formationhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600048Coarse-grained and All-atom Simulations towards the Early and Late Steps of Amyloid Fibril FormationMara Chiricotto, Thanh Thuy Tran, Phuong H. Nguyen, Simone Melchionna, Fabio Sterpone, Philippe Derreumaux2016-08-01T08:31:44.072754-05:00doi:10.1002/ijch.201600048John Wiley & Sons, Inc.10.1002/ijch.201600048http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600048Reviewn/an/aAbstract

Alzheimer's disease is the most common neurodegenerative disease. Experiments and computer simulations can complement one another to provide a full and in-depth understanding of many aspects in the amyloid field at the atomistic level. Here, we review results of our coarse-grained and all-atom simulations in aqueous solution aimed at determining: 1) early aggregation steps of short linear peptides; 2) nucleation size number; 3) solution structure of the Aβ1–40/Aβ1–42 wild-type dimers; 4) impact of FAD (familial forms of Alzheimer's disease) mutations on the structure of Aβ1–40/Aβ1–42 dimers; and 5) impact of protective mutations on the structure of Aβ1–40/Aβ1–42 dimers.

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]]> Alzheimer's disease is the most common neurodegenerative disease. Experiments and computer simulations can complement one another to provide a full and in-depth understanding of many aspects in the amyloid field at the atomistic level. Here, we review results of our coarse-grained and all-atom simulations in aqueous solution aimed at determining: 1) early aggregation steps of short linear peptides; 2) nucleation size number; 3) solution structure of the Aβ1–40/Aβ1–42 wild-type dimers; 4) impact of FAD (familial forms of Alzheimer's disease) mutations on the structure of Aβ1–40/Aβ1–42 dimers; and 5) impact of protective mutations on the structure of Aβ1–40/Aβ1–42 dimers. Whither Organic Synthesis?http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201500006Whither Organic Synthesis?Douglass F. Taber2015-04-15T14:10:41.245796-05:00doi:10.1002/ijch.201500006John Wiley & Sons, Inc.10.1002/ijch.201500006http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201500006Reviewn/an/aAbstract

An overview of the development of modern organic synthesis is given. Key researchers and their work are highlighted with a focus on the development of analytical and synthetic techniques currently in use.

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]]> An overview of the development of modern organic synthesis is given. Key researchers and their work are highlighted with a focus on the development of analytical and synthetic techniques currently in use. Cover Picture: (Isr. J. Chem. 6/2017)http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201780601Cover Picture: (Isr. J. Chem. 6/2017)2017-06-14T07:36:57.516316-05:00doi:10.1002/ijch.201780601John Wiley & Sons, Inc.10.1002/ijch.201780601http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201780601Cover Picture446446Thumbnail image of graphical abstract

The cover picture shows a TEM image and computer rendering of a multiwall GaS nanotube with its core filled with Pb. Details of this work are described in the paper “Structure and Stability of GaS Fullerenes and Nanotubes” by A. N. Enyashin et al., which is a part of this special issue dedicated to Computational Science of Inorganic Nanostructures.

]]>The cover picture shows a TEM image and computer rendering of a multiwall GaS nanotube with its core filled with Pb. Details of this work are described in the paper “Structure and Stability of GaS Fullerenes and Nanotubes” by A. N. Enyashin et al., which is a part of this special issue dedicated to Computational Science of Inorganic Nanostructures. Special Issue: Computational Science of Inorganic Nanostructureshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700015Special Issue: Computational Science of Inorganic NanostructuresReshef Tenne, Robert Evarestov2017-04-12T01:50:25.675593-05:00doi:10.1002/ijch.201700015John Wiley & Sons, Inc.10.1002/ijch.201700015http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201700015Guest Editorial448449Symmetry-based Study of MoS2 and WS2 Nanotubeshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600043Symmetry-based Study of MoS2 and WS2 NanotubesMilan Damnjanović, Tatjana Vuković, Ivanka Milošević2016-09-28T10:12:03.117591-05:00doi:10.1002/ijch.201600043John Wiley & Sons, Inc.10.1002/ijch.201600043http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600043Review450460Abstract

The symmetry-based study of MS2 (M=Mo, W) single-wall nanotubes (SWNTs) is reviewed. First, the structure and symmetry of MS2 NTs is determined. Then, conserved quantum numbers and general forms of potentials are derived. The valence force-field method implemented into the POLSym code is used to calculate phonon dispersions. Phonons characterized by a zero angular-momentum quantum number are studied in detail. The functional dependence of the frequency of rigid layer modes on NT diameter and chirality are found, and Raman- and infrared-active modes are singled out. Electronic band structure calculations are performed by the symmetry-based density functional tight-binding (DFTB) method. Changes in the band-gap type and size with NT chirality and diameter are evaluated. Optical absorption spectra of individual NTs are calculated using DFTB wave functions for exact transition matrix element calculations. Diffraction patterns of MS2 are predicted and NT characterization by different diffraction methods is discussed.

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]]> The symmetry-based study of MS2 (M=Mo, W) single-wall nanotubes (SWNTs) is reviewed. First, the structure and symmetry of MS2 NTs is determined. Then, conserved quantum numbers and general forms of potentials are derived. The valence force-field method implemented into the POLSym code is used to calculate phonon dispersions. Phonons characterized by a zero angular-momentum quantum number are studied in detail. The functional dependence of the frequency of rigid layer modes on NT diameter and chirality are found, and Raman- and infrared-active modes are singled out. Electronic band structure calculations are performed by the symmetry-based density functional tight-binding (DFTB) method. Changes in the band-gap type and size with NT chirality and diameter are evaluated. Optical absorption spectra of individual NTs are calculated using DFTB wave functions for exact transition matrix element calculations. Diffraction patterns of MS2 are predicted and NT characterization by different diffraction methods is discussed. Doped 1D Nanostructures of Transition-metal Oxides: First-principles Evaluation of Photocatalytic Suitabilityhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600099Doped 1D Nanostructures of Transition-metal Oxides: First-principles Evaluation of Photocatalytic SuitabilityYu. F. Zhukovskii, S. Piskunov, O. Lisovski, D. Bocharov, R. A. Evarestov2016-12-12T09:35:35.240006-05:00doi:10.1002/ijch.201600099John Wiley & Sons, Inc.10.1002/ijch.201600099http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600099Review461476Abstract

The splitting of water molecules under the influence of solar light on semiconducting electrodes is a clean and renewable source for the production of hydrogen fuel. Its efficiency depends on the relative position of the band-gap edges or the induced defect levels with a proper band alignment relative to the redox H+/H2 and O2/H2O potentials. For example, TiO2 and ZnO bulk, as well as thick slabs (whose band gaps are ∼3.2–3.4 eV), can be active only for photocatalytic applications under UV irradiation (possessing ∼1 % solar energy conversion efficiency). Nevertheless, by adjusting the band gap through formation of nanostructures and further doping, the efficiency can be increased up to ∼15 % (for 2.0–2.2 eV band gap). We analyse results of DFT (density functional theory) calculations on TiO2 nanotubes and ZnO nanowires, both pristine and doped (e.g., by AgZn, CO, FeTi, NO and SO substitutes). To reproduce the energies of one-electron states better, we have incorporated the Hartree-Fock (HF) exchange into the hybrid DFT+HF Hamiltonian. Both the atomic and electronic structure of nanomaterials, simulated by us, are analysed to evaluate their photocatalytic suitability, including positions of the redox potential levels inside the modified band gap, the width of which corresponds to visible-light energies. Analysis of the densities of states (DOS) for considered nanostructures clearly shows that photocatalytic properties can be significantly altered by dopants. The chosen hybrid methods of first-principles calculations significantly simplify selection of suitable nanomaterials possessing the required photocatalytic properties under solar light irradiation.

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]]> The splitting of water molecules under the influence of solar light on semiconducting electrodes is a clean and renewable source for the production of hydrogen fuel. Its efficiency depends on the relative position of the band-gap edges or the induced defect levels with a proper band alignment relative to the redox H+/H2 and O2/H2O potentials. For example, TiO2 and ZnO bulk, as well as thick slabs (whose band gaps are ∼3.2–3.4 eV), can be active only for photocatalytic applications under UV irradiation (possessing ∼1 % solar energy conversion efficiency). Nevertheless, by adjusting the band gap through formation of nanostructures and further doping, the efficiency can be increased up to ∼15 % (for 2.0–2.2 eV band gap). We analyse results of DFT (density functional theory) calculations on TiO2 nanotubes and ZnO nanowires, both pristine and doped (e.g., by AgZn, CO, FeTi, NO and SO substitutes). To reproduce the energies of one-electron states better, we have incorporated the Hartree-Fock (HF) exchange into the hybrid DFT+HF Hamiltonian. Both the atomic and electronic structure of nanomaterials, simulated by us, are analysed to evaluate their photocatalytic suitability, including positions of the redox potential levels inside the modified band gap, the width of which corresponds to visible-light energies. Analysis of the densities of states (DOS) for considered nanostructures clearly shows that photocatalytic properties can be significantly altered by dopants. The chosen hybrid methods of first-principles calculations significantly simplify selection of suitable nanomaterials possessing the required photocatalytic properties under solar light irradiation. Effects of Aliovalent Anion Substitution on the Electronic Structures and Properties of ZnO and CdShttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600120Effects of Aliovalent Anion Substitution on the Electronic Structures and Properties of ZnO and CdSSandhya Shenoy, Umesh V. Waghmare, S. R. Lingampalli, Anand Roy, C. N. R. Rao2016-11-16T04:46:42.137118-05:00doi:10.1002/ijch.201600120John Wiley & Sons, Inc.10.1002/ijch.201600120http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600120Review477489Abstract

Aliovalent anion substitution in ZnO, CdS, and related materials brings about drastic changes in their electronic structure and properties, making them colored, with a narrow band gap. Progressive substitution of N and F in ZnO leads to the formation of Zn2NF, with complete replacement of O with N and F. The band gaps of Zn2NF and O-doped Zn2NF are smaller than the band gap in ZnO, because N 2p states create a new sub-band above the valence band. Band-edge energies of these compounds are thermodynamically favorable for water splitting. First-principles calculations of P- and Cl-substituted CdS and ZnS show the presence of a band just above the valence band, due to the p orbitals of the trivalent dopant, resulting in a noticeable reduction in the band gap of these materials. Such substitution of anions can be quite effective in engineering the valence band, and hence, in tuning the related properties of materials. Complete substitution of S with P and Cl in CdS should result Cd2PCl, but the resulting material is Cd2PCl1.5 or Cd4P2Cl3. Cd4P2Cl3 shows a band gap of 2.36 eV and a photoluminescence band at 580 nm. First-principles calculations show it to be an effective photocatalyst for water splitting; it is shown experimentally to exhibit photocatalytic hydrogen evolution in the presence and absence of a sacrificial agent. Moreover, resilience to photocorrosion is a unique property of Cd4P2Cl3.

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]]> Aliovalent anion substitution in ZnO, CdS, and related materials brings about drastic changes in their electronic structure and properties, making them colored, with a narrow band gap. Progressive substitution of N and F in ZnO leads to the formation of Zn2NF, with complete replacement of O with N and F. The band gaps of Zn2NF and O-doped Zn2NF are smaller than the band gap in ZnO, because N 2p states create a new sub-band above the valence band. Band-edge energies of these compounds are thermodynamically favorable for water splitting. First-principles calculations of P- and Cl-substituted CdS and ZnS show the presence of a band just above the valence band, due to the p orbitals of the trivalent dopant, resulting in a noticeable reduction in the band gap of these materials. Such substitution of anions can be quite effective in engineering the valence band, and hence, in tuning the related properties of materials. Complete substitution of S with P and Cl in CdS should result Cd2PCl, but the resulting material is Cd2PCl1.5 or Cd4P2Cl3. Cd4P2Cl3 shows a band gap of 2.36 eV and a photoluminescence band at 580 nm. First-principles calculations show it to be an effective photocatalyst for water splitting; it is shown experimentally to exhibit photocatalytic hydrogen evolution in the presence and absence of a sacrificial agent. Moreover, resilience to photocorrosion is a unique property of Cd4P2Cl3. First-principles Calculations of InS-based Nanotubeshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600054First-principles Calculations of InS-based NanotubesAndrei V. Bandura, Dmitry D. Kuruch, Robert A. Evarestov2016-08-18T01:50:33.54405-05:00doi:10.1002/ijch.201600054John Wiley & Sons, Inc.10.1002/ijch.201600054http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600054Full Paper490500Abstract

We employed first-principles simulations using a hybrid exchange-correlation density functional PBE0 within an LCAO approximation to investigate the properties of InS single layers and nanotubes constructed from its stable orthorhombic and hypothetical hexagonal phases. We have found two types of 4-plane layers with relatively low formation energy, Rec4 and Hex4, which have been extracted from the orthorhombic and hexagonal phases, respectively. By rolling up Rec4 and Hex4 layers, the initial structures of single- and double-walled nanotubes have been generated. The nanotube formation and strain energies calculated after atomic relaxation show that the most stable structures can be obtained from the rectangular Rec4 nanosheets. At the same time, the double-walled nanotubes folded from the Rec4 nanosheets may be potentially useful for photocatalytic water splitting if they can really be synthesized.

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]]> We employed first-principles simulations using a hybrid exchange-correlation density functional PBE0 within an LCAO approximation to investigate the properties of InS single layers and nanotubes constructed from its stable orthorhombic and hypothetical hexagonal phases. We have found two types of 4-plane layers with relatively low formation energy, Rec4 and Hex4, which have been extracted from the orthorhombic and hexagonal phases, respectively. By rolling up Rec4 and Hex4 layers, the initial structures of single- and double-walled nanotubes have been generated. The nanotube formation and strain energies calculated after atomic relaxation show that the most stable structures can be obtained from the rectangular Rec4 nanosheets. At the same time, the double-walled nanotubes folded from the Rec4 nanosheets may be potentially useful for photocatalytic water splitting if they can really be synthesized. Capillary Imbibition of Gadolinium Halides into WS2 Nanotubes: a Molecular Dynamics Viewhttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600055Capillary Imbibition of Gadolinium Halides into WS2 Nanotubes: a Molecular Dynamics ViewFrancis Leonard Deepak, Andrey N. Enyashin2016-08-25T08:40:29.486739-05:00doi:10.1002/ijch.201600055John Wiley & Sons, Inc.10.1002/ijch.201600055http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600055Full Paper501508Abstract

The structure of the molten salts GdX3, where X denotes Cl, Br, or I, and the kinetics of their penetration into WS2 nanotubes were investigated using molecular dynamics simulations. The GdCl3 and GdBr3 melts are found to comprise an amorphous framework structure with substantial intermediate-range ordering, as manifested by pair distribution, and angle-resolved pair-pair distribution functions associated with cationic correlations. In contrast, the GdI3 melt is a liquid with short-range cationic ordering. These structural peculiarities cause dramatically different mobility of Gd cations among pure GdX3 melts and explain the relative difference in the capillary activity of WS2 nanotubes regarding the melts, as observed in preliminary experiments. Extended MD simulations of GdCl3 dissolved in molten KCl predict the total degradation of the GdCl3 framework structure below 40 mol %, although no essential uptake of Gd cations by the WS2 nanotube is observed, due to more progressive diffusion of K cations. Our theory suggests that, among the considered halides, only the GdI3 compound is suitable for Gd encapsulation into WS2 nanotubes employing the capillary technique.

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]]> The structure of the molten salts GdX3, where X denotes Cl, Br, or I, and the kinetics of their penetration into WS2 nanotubes were investigated using molecular dynamics simulations. The GdCl3 and GdBr3 melts are found to comprise an amorphous framework structure with substantial intermediate-range ordering, as manifested by pair distribution, and angle-resolved pair-pair distribution functions associated with cationic correlations. In contrast, the GdI3 melt is a liquid with short-range cationic ordering. These structural peculiarities cause dramatically different mobility of Gd cations among pure GdX3 melts and explain the relative difference in the capillary activity of WS2 nanotubes regarding the melts, as observed in preliminary experiments. Extended MD simulations of GdCl3 dissolved in molten KCl predict the total degradation of the GdCl3 framework structure below 40 mol %, although no essential uptake of Gd cations by the WS2 nanotube is observed, due to more progressive diffusion of K cations. Our theory suggests that, among the considered halides, only the GdI3 compound is suitable for Gd encapsulation into WS2 nanotubes employing the capillary technique. First-principles Study of Perovskite Ultrathin Films: Stability and Confinement Effectshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600056First-principles Study of Perovskite Ultrathin Films: Stability and Confinement EffectsMarco Arrigoni, Eugene A. Kotomin, Joachim Maier2016-11-15T08:27:26.74198-05:00doi:10.1002/ijch.201600056John Wiley & Sons, Inc.10.1002/ijch.201600056http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600056Full Paper509521Abstract

In this first-principles study we investigate the atomic, electronic, and vibrational structure of BaZrO3(001) ultrathin films and surfaces, using a hybrid functional and a local Gaussian-like basis set. The low-index nonpolar (001) surface is known to be the most stable. We considered both possible kinds of nonpolar terminations (BaO and ZrO2) for the (001) surface. The systems were studied using a slab model. Ultrathin films were modeled using slabs with the number of atomic planes ranging from three to seven, whereas surfaces were modeled with much thicker slabs composed of 15 atomic planes. In order to estimate the Gibbs free energy at finite temperatures, lattice vibrational frequencies were also calculated. We found that phonons noticeably affect the relative thermodynamic stability of the two termination layers: while at room temperature the BaO termination has the lowest energy, at intermediate temperatures (500 K) both terminations can coexist, and at higher temperatures (900 K) the ZrO2-terminated surface becomes the most stable. We considered the effect of two-dimensional confinement on the structural, electronic, and vibrational properties of these ultrathin films. We found these confinement effects to be short ranged, with the properties of three-plane films to be the only ones that noticeably differ from the bulk material. Finally, we briefly consider confinement effects in such ultrathin films containing neutral and fully charged oxygen vacancies (charge states 0 and +2). We show, in particular, how lattice vibrations affect the Gibbs formation energy of a neutral oxygen vacancy making it completely independent of the film thickness at high temperatures (1000 K), due to cancellation of enthalpy and entropy contributions.

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]]> In this first-principles study we investigate the atomic, electronic, and vibrational structure of BaZrO3(001) ultrathin films and surfaces, using a hybrid functional and a local Gaussian-like basis set. The low-index nonpolar (001) surface is known to be the most stable. We considered both possible kinds of nonpolar terminations (BaO and ZrO2) for the (001) surface. The systems were studied using a slab model. Ultrathin films were modeled using slabs with the number of atomic planes ranging from three to seven, whereas surfaces were modeled with much thicker slabs composed of 15 atomic planes. In order to estimate the Gibbs free energy at finite temperatures, lattice vibrational frequencies were also calculated. We found that phonons noticeably affect the relative thermodynamic stability of the two termination layers: while at room temperature the BaO termination has the lowest energy, at intermediate temperatures (500 K) both terminations can coexist, and at higher temperatures (900 K) the ZrO2-terminated surface becomes the most stable. We considered the effect of two-dimensional confinement on the structural, electronic, and vibrational properties of these ultrathin films. We found these confinement effects to be short ranged, with the properties of three-plane films to be the only ones that noticeably differ from the bulk material. Finally, we briefly consider confinement effects in such ultrathin films containing neutral and fully charged oxygen vacancies (charge states 0 and +2). We show, in particular, how lattice vibrations affect the Gibbs formation energy of a neutral oxygen vacancy making it completely independent of the film thickness at high temperatures (1000 K), due to cancellation of enthalpy and entropy contributions. First-principles Studies of the Electronic and Thermoelectric Properties of Misfit Layered Phases of Calcium Cobaltitehttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600065First-principles Studies of the Electronic and Thermoelectric Properties of Misfit Layered Phases of Calcium CobaltiteAshwin Ramasubramaniam2016-11-09T16:00:50.712915-05:00doi:10.1002/ijch.201600065John Wiley & Sons, Inc.10.1002/ijch.201600065http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600065Full Paper522528Abstract

The electronic and thermoelectric properties of two phases of calcium cobaltite, a misfit layered compound, are investigated and compared using first-principles DFT calculations. The two phases considered here include the conventional bulk phase that consists of alternating layers of Ca2CoO3 and CoO2, and a new phase that consists of alternating layers of CaCoO2 and CoO2, which was recently discovered in nanotubes. Electronic structure calculations reveal that both phases are ferrimagnetic materials with one important difference: the bulk phase is metallic, whereas the nanotubular phase is semiconducting. The metal-to-semiconductor transition that accompanies the Ca2CoO3 to CaCoO2 structural transition is shown to arise from the depletion of free carriers from the donor Ca atoms. The implications of the difference in electronic structure for the thermoelectric performance of these two phases are further examined with Boltzmann transport calculations. Relative to the metallic phase, the semiconducting phase displays appreciably higher Seebeck coefficients at minimal doping levels; these increased Seebeck coefficients compensate for the reduced conductivity and result in large power factors. In conjunction with the fact that the semiconducting phase is peculiar to 1D nanotubes, it is expected that additional effects from quantum confinement could render these low-dimensional materials as promising thermoelectric materials.

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]]> The electronic and thermoelectric properties of two phases of calcium cobaltite, a misfit layered compound, are investigated and compared using first-principles DFT calculations. The two phases considered here include the conventional bulk phase that consists of alternating layers of Ca2CoO3 and CoO2, and a new phase that consists of alternating layers of CaCoO2 and CoO2, which was recently discovered in nanotubes. Electronic structure calculations reveal that both phases are ferrimagnetic materials with one important difference: the bulk phase is metallic, whereas the nanotubular phase is semiconducting. The metal-to-semiconductor transition that accompanies the Ca2CoO3 to CaCoO2 structural transition is shown to arise from the depletion of free carriers from the donor Ca atoms. The implications of the difference in electronic structure for the thermoelectric performance of these two phases are further examined with Boltzmann transport calculations. Relative to the metallic phase, the semiconducting phase displays appreciably higher Seebeck coefficients at minimal doping levels; these increased Seebeck coefficients compensate for the reduced conductivity and result in large power factors. In conjunction with the fact that the semiconducting phase is peculiar to 1D nanotubes, it is expected that additional effects from quantum confinement could render these low-dimensional materials as promising thermoelectric materials. Structure and Stability of GaS Fullerenes and Nanotubeshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600121Structure and Stability of GaS Fullerenes and NanotubesAndrey N. Enyashin, Olga Brontvein, Gotthard Seifert, Reshef Tenne2016-12-28T03:55:31.20995-05:00doi:10.1002/ijch.201600121John Wiley & Sons, Inc.10.1002/ijch.201600121http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600121Full Paper529539Abstract

Recently, polyhedral; octahedral fullerene-like structures and cylindrical nanotubes of gallium sulfide have been produced in far from equilibrium conditions using a high power solar synthesis and Pb as growth promoter. Their exact atomistic structure and their formation path remain unknown. Here, the models of fullerenes and nanotubes are designed for both stable β- and metastable γ-polymorphs of GaS. Their stability and electronic properties were investigated as a function of both the morphology and size using density-functional tight-binding method. The results manifest that, construction principles for GaS fullerenes are different from those for “classical” dichalcogenide fullerenes. In contrast to the bulk, the kinetic stability of fullerene-like structures of the γ-GaS phase is found to be larger, than that for β-GaS which is ascribed to a sterical specificity of intersected γ-GaS layers. We predict that, the γ-GaS phase should arise at least as an intermediate state during the synthesis of polyhedral GaS nanoparticles. Notwithstanding the polymorphic type, the size and the morphology of GaS nanostructures, they are all semiconductors. Finally, the possible composition and electronic properties of Pb||GaS interface within the Pb@GaS nanoparticles are discussed.

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]]> Recently, polyhedral; octahedral fullerene-like structures and cylindrical nanotubes of gallium sulfide have been produced in far from equilibrium conditions using a high power solar synthesis and Pb as growth promoter. Their exact atomistic structure and their formation path remain unknown. Here, the models of fullerenes and nanotubes are designed for both stable β- and metastable γ-polymorphs of GaS. Their stability and electronic properties were investigated as a function of both the morphology and size using density-functional tight-binding method. The results manifest that, construction principles for GaS fullerenes are different from those for “classical” dichalcogenide fullerenes. In contrast to the bulk, the kinetic stability of fullerene-like structures of the γ-GaS phase is found to be larger, than that for β-GaS which is ascribed to a sterical specificity of intersected γ-GaS layers. We predict that, the γ-GaS phase should arise at least as an intermediate state during the synthesis of polyhedral GaS nanoparticles. Notwithstanding the polymorphic type, the size and the morphology of GaS nanostructures, they are all semiconductors. Finally, the possible composition and electronic properties of Pb||GaS interface within the Pb@GaS nanoparticles are discussed. Ab initio Modelling of Plasmons in Metal-semiconductor Bilayer Transition-metal Dichalcogenide Heterostructureshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600122Ab initio Modelling of Plasmons in Metal-semiconductor Bilayer Transition-metal Dichalcogenide HeterostructuresHuseyin Sener Sen, Lede Xian, Felipe H. da Jornada, Steven G. Louie, Angel Rubio2017-01-24T03:15:54.42135-05:00doi:10.1002/ijch.201600122John Wiley & Sons, Inc.10.1002/ijch.201600122http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600122Full Paper540546Abstract

Two-dimensional transition-metal dichalcogenides (TMDs) have attracted enormous interest, due to the richness of their optical and electronic properties. Here, we consider two prototypical two-dimensional TMD metal-semiconductor bilayer heterostructures, VSe2-MoSe2 and VSe2-WSe2, and investigate the effect of the semiconducting layer on the plasmons supported by the metallic layer using first principles time-dependent density functional theory (TDDFT) calculations. We focus on the flat region of the plasmon dispersion, where momentum transfer is larger than 0.05 Å−1 and the interband transitions gain importance. With the addition of the semiconducting layer, we show that the electronic band structure undergoes significant changes close to the Fermi level, and hybridization occurs, which leads to strengthening of the interband transitions and a significant redshift in the plasmon energy.

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]]> Two-dimensional transition-metal dichalcogenides (TMDs) have attracted enormous interest, due to the richness of their optical and electronic properties. Here, we consider two prototypical two-dimensional TMD metal-semiconductor bilayer heterostructures, VSe2-MoSe2 and VSe2-WSe2, and investigate the effect of the semiconducting layer on the plasmons supported by the metallic layer using first principles time-dependent density functional theory (TDDFT) calculations. We focus on the flat region of the plasmon dispersion, where momentum transfer is larger than 0.05 Å−1 and the interband transitions gain importance. With the addition of the semiconducting layer, we show that the electronic band structure undergoes significant changes close to the Fermi level, and hybridization occurs, which leads to strengthening of the interband transitions and a significant redshift in the plasmon energy. Engineering the Fullerene-protein Interface by Computational Design: The Sum is More than its Partshttp://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600127Engineering the Fullerene-protein Interface by Computational Design: The Sum is More than its PartsFrancesco Trozzi, Tainah Dorina Marforio, Andrea Bottoni, Francesco Zerbetto, Matteo Calvaresi2016-12-22T04:30:29.94106-05:00doi:10.1002/ijch.201600127John Wiley & Sons, Inc.10.1002/ijch.201600127http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600127Full Paper547552Abstract

Of all the amino acids, the surface of π-electron conjugated carbon nanoparticles has the largest affinity for tryptophan, followed by tyrosine, phenylalanine, and histidine. In order to increase the binding of a protein to a fullerene, it should suffice to mutate a residue of the site that binds to the fullerene to tryptophan, Trp. Computational chemistry shows that this intuitive approach is fraught with danger. Mutation of a binding residue to Trp may even destabilize the binding because of the complicated balance between van der Waals, polar and non-polar solvation interactions.

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]]> Of all the amino acids, the surface of π-electron conjugated carbon nanoparticles has the largest affinity for tryptophan, followed by tyrosine, phenylalanine, and histidine. In order to increase the binding of a protein to a fullerene, it should suffice to mutate a residue of the site that binds to the fullerene to tryptophan, Trp. Computational chemistry shows that this intuitive approach is fraught with danger. Mutation of a binding residue to Trp may even destabilize the binding because of the complicated balance between van der Waals, polar and non-polar solvation interactions. Charge Transfer Variability in Misfit Layer Compounds: Comparison of SnS-SnS2 and LaS-TaS2http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600148Charge Transfer Variability in Misfit Layer Compounds: Comparison of SnS-SnS2 and LaS-TaS2Tommy Lorenz, Igor A. Baburin, Jan-Ole Joswig, Gotthard Seifert2017-02-01T02:35:36.191542-05:00doi:10.1002/ijch.201600148John Wiley & Sons, Inc.10.1002/ijch.201600148http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1002%2Fijch.201600148Full Paper553559Abstract

The present paper compares and discusses two selected misfit (layer) compounds exemplarily, namely SnS-SnS2 and LaS-TaS2. We have employed a density-functional theory-based approach to calculate structural, energetic, and electronic properties of these structures. We have put emphasis on the difference between single layers, combined double-layer systems and periodically stacked bulk structures. Especially the varying magnitudes of charge transfer between the sublayers were studied. We demonstrate how the chemical constitution of the sublayers affects the interlayer interactions: these may be a weak non-bonding van-der-Waals dominated interlayer interaction as in SnS-SnS2 and many other layered structures or a strong interaction related to a remarkable charge transfer between the layers as in LaS-TaS2.

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]]> The present paper compares and discusses two selected misfit (layer) compounds exemplarily, namely SnS-SnS2 and LaS-TaS2. We have employed a density-functional theory-based approach to calculate structural, energetic, and electronic properties of these structures. We have put emphasis on the difference between single layers, combined double-layer systems and periodically stacked bulk structures. Especially the varying magnitudes of charge transfer between the sublayers were studied. We demonstrate how the chemical constitution of the sublayers affects the interlayer interactions: these may be a weak non-bonding van-der-Waals dominated interlayer interaction as in SnS-SnS2 and many other layered structures or a strong interaction related to a remarkable charge transfer between the layers as in LaS-TaS2.