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Nature Chemistry

Aurélie Mousnier, Andrew S Bell, Dawid P Swieboda, Julia Morales-Sanfrutos, Inmaculada Pérez-Dorado, James A Brannigan, Joseph Newman, Markus Ritzefeld, Jennie A Hutton, Anabel Guedán, Amin S Asfor, Sean W Robinson, Iva Hopkins-Navratilova, Anthony J Wilkinson, Sebastian L Johnston, Robin J Leatherbarrow, Tobias J Tuthill, Roberto Solari, Edward W Tate
Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry...
May 14, 2018: Nature Chemistry
Yueqin Zheng, Xingyue Ji, Bingchen Yu, Kaili Ji, David Gallo, Eva Csizmadia, Mengyuan Zhu, Manjusha Roy Choudhury, Ladie Kimberly C De La Cruz, Vayou Chittavong, Zhixiang Pan, Zhengnan Yuan, Leo E Otterbein, Binghe Wang
Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction...
May 14, 2018: Nature Chemistry
Johnny Habchi, Sean Chia, Céline Galvagnion, Thomas C T Michaels, Mathias M J Bellaiche, Francesco Simone Ruggeri, Michele Sanguanini, Ilaria Idini, Janet R Kumita, Emma Sparr, Sara Linse, Christopher M Dobson, Tuomas P J Knowles, Michele Vendruscolo
Alzheimer's disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-β peptide. Although increasing evidence implicates cholesterol in the pathogenesis of Alzheimer's disease, the detailed mechanistic link between this lipid molecule and the disease process remains to be fully established. To address this problem, we adopt a kinetics-based strategy that reveals a specific catalytic role of cholesterol in the aggregation of Aβ42 (the 42-residue form of the amyloid-β peptide)...
May 7, 2018: Nature Chemistry
Youngsoo Kim, Jeremy G Smith, Prashant K Jain
Multi-electron redox reactions, although central to artificial photosynthesis, are kinetically sluggish. Amidst the search for synthetic catalysts for such processes, plasmonic nanoparticles have been found to catalyse multi-electron reduction of CO2 under visible light. This example motivates the need for a general, insight-driven framework for plasmonic catalysis of such multi-electron chemistry. Here, we elucidate the principles underlying the extraction of multiple redox equivalents from a plasmonic photocatalyst...
May 7, 2018: Nature Chemistry
Guosheng Shi, Liang Chen, Yizhou Yang, Deyuan Li, Zhe Qian, Shanshan Liang, Long Yan, Lu Hua Li, Minghong Wu, Haiping Fang
NaCl in a 1:1 stoichiometry is the only known stable form of the Na-Cl crystal under ambient conditions, and non-1:1 Na-Cl species can only form under extreme conditions, such as high pressures. Here we report the direct observation, under ambient conditions, of Na2 Cl and Na3 Cl as two-dimensional (2D) Na-Cl crystals, together with regular NaCl, on reduced graphene oxide membranes and on the surfaces of natural graphite powders from salt solutions far below the saturated concentration. Molecular dynamics and density functional theory calculations suggest that this unconventional crystallization process originates from the cation-π interaction between the ions and the π-conjugated system in the graphitic surface, which promotes the ion-surface adsorption...
May 7, 2018: Nature Chemistry
Joseph R Clark, Kaibo Feng, Anasheh Sookezian, M Christina White
Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity...
April 30, 2018: Nature Chemistry
Robert Alberstein, Yuta Suzuki, Francesco Paesani, F Akif Tezcan
De novo design and construction of stimuli-responsive protein assemblies that predictably switch between discrete conformational states remains an essential but highly challenging goal in biomolecular design. We previously reported synthetic, two-dimensional protein lattices self-assembled via disulfide bonding interactions, which endows them with a unique capacity to undergo coherent conformational changes without losing crystalline order. Here, we carried out all-atom molecular dynamics simulations to map the free-energy landscape of these lattices, validated this landscape through extensive structural characterization by electron microscopy and established that it is predominantly governed by solvent reorganization entropy...
April 30, 2018: Nature Chemistry
Sangram S Kale, Camille Villequey, Xu-Dong Kong, Alessandro Zorzi, Kaycie Deyle, Christian Heinis
Successful screening campaigns depend on large and structurally diverse collections of compounds. In macrocycle screening, variation of the molecular scaffold is important for structural diversity, but so far it has been challenging to diversify this aspect in large combinatorial libraries. Here, we report the cyclization of peptides with two chemical bridges to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Application of this strategy to phage-encoded libraries allowed for the screening of an unprecedented structural diversity of macrocycles against plasma kallikrein, which is important in the swelling disorder hereditary angioedema...
April 30, 2018: Nature Chemistry
Mijanur Rahaman Molla, Poornima Rangadurai, Lucas Antony, Subramani Swaminathan, Juan J de Pablo, S Thayumanavan
Nature has engineered exquisitely responsive systems where molecular-scale information is transferred across an interface and propagated over long length scales. Such systems rely on multiple interacting, signalling and adaptable molecular and supramolecular networks that are built on dynamic, non-equilibrium structures. Comparable synthetic systems are still in their infancy. Here, we demonstrate that the light-induced actuation of a molecularly thin interfacial layer, assembled from a hydrophilic- azobenzene -hydrophobic diblock copolymer, can result in a reversible, long-lived perturbation of a robust glassy membrane across a range of over 500 chemical bonds...
April 30, 2018: Nature Chemistry
Tyler J Wadzinski, Angela Steinauer, Liana Hie, Guillaume Pelletier, Alanna Schepartz, Scott J Miller
Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides...
April 30, 2018: Nature Chemistry
Randolph Lopez, Ruofan Wang, Georg Seelig
Despite its early promise as a diagnostic and prognostic tool, gene expression profiling remains cost-prohibitive and challenging to implement in a clinical setting. Here, we introduce a molecular computation strategy for analysing the information contained in complex gene expression signatures without the need for costly instrumentation. Our workflow begins by training a computational classifier on labelled gene expression data. This in silico classifier is then realized at the molecular level to enable expression analysis and classification of previously uncharacterized samples...
April 30, 2018: Nature Chemistry
Mohit Kumar, Nicole L Ing, Vishal Narang, Nadeesha K Wijerathne, Allon I Hochbaum, Rein V Ulijn
Aqueous compatible supramolecular materials hold promise for applications in environmental remediation, energy harvesting and biomedicine. One remaining challenge is to actively select a target structure from a multitude of possible options, in response to chemical signals, while maintaining constant, physiological conditions. Here, we demonstrate the use of amino acids to actively decorate a self-assembling core molecule in situ, thereby controlling its amphiphilicity and consequent mode of assembly. The core molecule is the organic semiconductor naphthalene diimide, functionalized with D- and L- tyrosine methyl esters as competing reactive sites...
April 30, 2018: Nature Chemistry
Kelong Zhu, Giorgio Baggi, Stephen J Loeb
Mechanically interlocked molecules such as rotaxanes and catenanes comprise two or more components whose motion relative to each other can be controlled. A [2]rotaxane molecular shuttle, for example, consists of an axle bearing two recognition sites and a single macrocyclic wheel that can undergo a to-and-fro motion along the axle-shuttling between the recognition sites. The ability of mechanically interlocked molecules to undergo this type of large-amplitude change is the core mechanism behind almost every interlocked molecular switch or machine, including sophisticated mechanical systems such as a molecular elevator and a peptide synthesizer...
April 30, 2018: Nature Chemistry
Meng Wang, Chunlei Jiang, Songquan Zhang, Xiaohe Song, Yongbing Tang, Hui-Ming Cheng
Calcium-ion batteries (CIBs) are attractive candidates for energy storage because Ca2+ has low polarization and a reduction potential (-2.87 V versus standard hydrogen electrode, SHE) close to that of Li+ (-3.04 V versus SHE), promising a wide voltage window for a full battery. However, their development is limited by difficulties such as the lack of proper cathode/anode materials for reversible Ca2+ intercalation/de-intercalation, low working voltages (<2 V), low cycling stability, and especially poor room-temperature performance...
April 23, 2018: Nature Chemistry
Daofu Yuan, Shengrui Yu, Wentao Chen, Jiwei Sang, Chang Luo, Tao Wang, Xin Xu, Piergiorgio Casavecchia, Xingan Wang, Zhigang Sun, Dong H Zhang, Xueming Yang
Accurate measurements of product state-resolved angular distributions are central to fundamental studies of chemical reaction dynamics. Yet, fine quantum-mechanical structures in product angular distributions of a reactive scattering process, such as the fast oscillations in the forward-scattering direction, have never been observed experimentally and the nature of these oscillations has not been fully explored. Here we report the crossed-molecular-beam experimental observation of these fast forward-scattering oscillations in the product angular distribution of the benchmark chemical reaction, H + HD → H2  + D...
April 23, 2018: Nature Chemistry
Mahdi Zeraati, David B Langley, Peter Schofield, Aaron L Moye, Romain Rouet, William E Hughes, Tracy M Bryan, Marcel E Dinger, Daniel Christ
Human genome function is underpinned by the primary storage of genetic information in canonical B-form DNA, with a second layer of DNA structure providing regulatory control. I-motif structures are thought to form in cytosine-rich regions of the genome and to have regulatory functions; however, in vivo evidence for the existence of such structures has so far remained elusive. Here we report the generation and characterization of an antibody fragment (iMab) that recognizes i-motif structures with high selectivity and affinity, enabling the detection of i-motifs in the nuclei of human cells...
April 23, 2018: Nature Chemistry
William E Perreault, Nandini Mukherjee, Richard N Zare
Molecular interactions are best probed by scattering experiments. Interpretation of these studies has been limited by lack of control over the quantum states of the incoming collision partners. We report here the rotationally inelastic collisions of quantum-state prepared deuterium hydride (HD) with H2 and D2 using a method that provides an improved control over the input states. HD was coexpanded with its partner in a single supersonic beam, which reduced the collision temperature to 0-5 K, and thereby restricted the involved incoming partial waves to s and p...
April 16, 2018: Nature Chemistry
Kazuki Tanifuji, Chi Chung Lee, Nathaniel S Sickerman, Kazuyuki Tatsumi, Yasuhiro Ohki, Yilin Hu, Markus W Ribbe
The M-cluster is the [(homocitrate)MoFe7 S9 C] active site of nitrogenase that is derived from an 8Fe core assembled viacoupling and rearrangement of two [Fe4 S4 ] clusters concomitant with the insertion of an interstitial carbon and a 'ninth sulfur'. Combining synthetic [Fe4 S4 ] clusters with an assembly protein template, here we show that sulfite can give rise to the ninth sulfur that is incorporated in the catalytically important belt region of the cofactor after the radical S-adenosyl-L-methionine-dependent carbide insertion and the concurrent 8Fe-core rearrangement have already taken place...
April 16, 2018: Nature Chemistry
Astrid Bergeat, Simon Chefdeville, Michel Costes, Sébastien B Morales, Christian Naulin, Uzi Even, Jacek Kłos, François Lique
Inelastic collisions that occur between open-shell atoms and other atoms or molecules, and that promote a spin-orbit transition, involve multiple interaction potentials. They are non-adiabatic by nature and cannot be described within the Born-Oppenheimer approximation; in particular, their theoretical modelling becomes very challenging when the collision energies have values comparable to the spin-orbit splitting. Here we study inelastic collisions between carbon in its ground state C(3 Pj=0 ) and helium atoms-at collision energies in the vicinity of spin-orbit excitation thresholds (~0...
April 16, 2018: Nature Chemistry
Amit A Nagarkar, Andreas F M Kilbinger
We the authors are retracting this Article because of our failure to reproduce the molecular weight dispersities (PDI) shown in Fig. 4 using the chain-transfer agent described in the paper (CTA1). While the degenerate chain-transfer mechanism described in Fig. 3 is correct, the best molecular weight dispersities that could be reproduced with the chain-transfer agent shown in the Article are much larger (PDI > 2.0) than reported.We have since studied the kinetics of CTA1 in comparison with several other chain-transfer agents we are currently investigating and we now understand that the reactivity of CTA1 towards propagating ruthenium alkylidene complexes is very low...
April 11, 2018: Nature Chemistry
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