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https://www.readbyqxmd.com/read/28213525/conformational-profiling-of-the-at1-angiotensin-ii-receptor-reflects-biased-agonism-g-protein-coupling-and-cellular-context
#1
Dominic Devost, Rory Sleno, Darlaine Petrin, Alice Zhang, Yuji Shinjo, Rakan Okde, Junken Aoki, Asuka Inoue, Terence E Hebert
Here, we report the design and use of GPCR-based biosensors to monitor ligand-mediated conformational changes in receptors in intact cells. These biosensors use Bioluminescence Resonance Energy Transfer (BRET) with Renilla luciferase (RlucII) as an energy donor, placed at the distal end of the receptor C-tail and the small fluorescent molecule FlAsH, as an energy acceptor, its binding site inserted at different positions throughout the intracellular loops and carboxy-terminal tail of the angiotensin II type I receptor (AT1R)...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28211697/benchmarking-density-functionals-for-chemical-bonds-of-gold
#2
Kasper Planeta Kepp
Gold plays a major role in nanochemistry, catalysis, and electrochemistry. Accordingly, hundreds of studies apply density functionals to study chemical bonding with gold, yet there is no systematic attempt to assess the accuracy of these methods applied to gold. This paper reports a benchmark against 51 experimental bond enthalpies of AuX systems and seven additional polyatomic and cationic molecules. 12 density functionals were tested, covering meta functionals, hybrids with variable HF exchange, double-hybrid, dispersion-corrected and non-hybrid GGA functionals...
February 17, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28207811/accelerated-flexible-protein-ligand-docking-using-hamiltonian-replica-exchange-with-a-repulsive-biasing-potential
#3
Katja Ostermeir, Martin Zacharias
A molecular dynamics replica exchange based method has been developed that allows rapid identification of putative ligand binding sites on the surface of biomolecules. The approach employs a set of ambiguity restraints in replica simulations between receptor and ligand that allow close contacts in the reference replica but promotes transient dissociation in higher replicas. This avoids long-lived trapping of the ligand or partner proteins at nonspecific, sticky, sites on the receptor molecule and results in accelerated exploration of the possible binding regions...
2017: PloS One
https://www.readbyqxmd.com/read/28201891/electron-transport-through-a-spin-crossover-junction-perspectives-from-a-wavefunction-based-approach
#4
Sergi Vela, Martin Verot, Emmanuel Fromager, Vincent Robert
The present paper reports the application of a computational framework, based on the quantum master equation, the Fermi's golden Rule, and conventional wavefunction-based methods, to describe electron transport through a spin crossover molecular junction (Fe(bapbpy) (NCS)2, 1, bapbpy = N-(6-(6-(Pyridin-2-ylamino)pyridin-2-yl)pyridin-2-yl)-pyridin-2-amine). This scheme is an alternative to the standard approaches based on the relative position and nature of the frontier orbitals, as it evaluates the junction's Green's function by means of accurate state energies and wavefunctions...
February 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28199103/using-the-k-d-tree-data-structure-to-accelerate-monte-carlo-simulations
#5
Qile Paul Chen, Bai Xue, J Ilja Siepmann
The k-d tree data structure is implemented in a Monte Carlo (MC) molecular simulation program to accelerate the range search for particles or interaction sites within the cutoff distance when Lennard-Jones and Coulomb interactions are computed. MC simulations are performed for different molecules in various ensembles to assess the efficiency enhancements due to the k-d tree data structure. It is found that the use of k-d trees accelerates significantly simulations for Lennard-Jones particles in the NVT and NVT-Gibbs ensembles and for n-butane and 2,4,6,8,10,12,14,16,18,20,22-undecamethylpentacosane represented by the TraPPE-UA force field in the NpT ensemble...
February 15, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28198627/intermode-coupling-drives-the-irreversible-tautomerization-in-porphycene-on-copper-111-induced-by-scanning-tunnelling-microscopy
#6
Dino Novko, María Blanco-Rey, Jean Christophe Tremblay
In this contribution, we develop a nonadiabatic theory that explains, from first-principles, the recently reported irreversible trans → cis tautomerization of porphycene on Cu(111) induced by a scanning tunnelling microscope at finite bias. The inelastic contribution to the STM current is found to excite a large number of skeletal vibrational modes of the molecule, thereby inducing a deformation of the potential energy landscape along the hydrogen transfer coordinate. Above a threshold bias, the stability of the tautomers is reversed, which indirectly drives the reaction via intermode coupling...
February 17, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28198504/complete-mitochondrial-genome-of-the-amur-hedgehog-erinaceus-amurensis-erinaceidae-and-higher-phylogeny-of-the-family-erinaceidae
#7
N H Kim, S J Lim, H M Chae, Y C Park
We sequenced and characterized the complete mitogenome (KX964606) of the Amur hedgehog Erinaceus amurensis to provide more data for comparative mitogenomics of the genus Erinaceus (Erinaceidae). The mitogenome of E. amurensis is a circular molecule 16,941 bp long, consisting of a control region and a conserved set of 37 genes containing 13 protein-coding genes, 22 tRNA genes, and two rRNA genes (12S rRNA and 16S rRNA). The mitogenome of E. amurensis is AT-biased, with a nucleotide composition of 33.9% A, 21...
February 8, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28196116/the-scoring-bias-in-reverse-docking-and-the-score-normalization-strategy-to-improve-success-rate-of-target-fishing
#8
Qiyao Luo, Liang Zhao, Jianxing Hu, Hongwei Jin, Zhenming Liu, Liangren Zhang
Target fishing often relies on the use of reverse docking to identify potential target proteins of ligands from protein database. The limitation of reverse docking is the accuracy of current scoring funtions used to distinguish true target from non-target proteins. Many contemporary scoring functions are designed for the virtual screening of small molecules without special optimization for reverse docking, which would be easily influenced by the properties of protein pockets, resulting in scoring bias to the proteins with certain properties...
2017: PloS One
https://www.readbyqxmd.com/read/28193575/applying-sewage-epidemiology-approach-to-estimate-illicit-drug-consumption-in-a-tropical-context-bias-related-to-sewage-temperature-and-ph
#9
Damien A Devault, Yves Lévi, Sara Karolak
Illicit drug consumption can be estimated from drug target residue (DTR) in wastewater, with the reliability of results being partly linked to DTR stability in the sewage network. However, wastewater temperature and pH drive the stability of molecules and, in this context, tropical conditions must be studied to specify the impact of residence time in the sewage network on DTR degradation. Warmth enhances biotic and abiotic processes such as degradation, leading to a decrease in oxygen content, and consequently, early diagenesis conditions in wastewater...
February 10, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28192940/analysis-of-tertiary-interactions-between-sart3-and-u6-small-nuclear-rna-using-modified-nanocapillaries
#10
Choongman Lee, Joon Kyu Park, Yeoan Youn, Joo Hyoung Kim, Kyo-Seok Lee, Nak-Kyoon Kim, Eunji Kim, Eunice Eunkyeong Kim, Kyung-Hwa Yoo
We employed modified glass nanocapillaries to investigate interactions between the RNA-binding protein, known as cell carcinoma antigen recognized by T cells-3 (SART3), and the noncoding spliceosome component, U6 small nuclear RNA (snRNA), at the single-molecule level. We functionalized the nanocapillaries with U6 snRNA fragments, which were hybridized to DNA molecules and then covalently attached to the nanocapillary surface. When transported through the modified nanocapillaries, two different SART3-derived constructs, HAT-RRM1-RRM2 and RRM1-RRM2, exhibited resistive ionic current pulses with different dwell times, which represented their different binding affinities to tethered U6 snRNAs...
February 9, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28191772/human-induced-pluripotent-cell-derived-sensory-neurons-for-fate-commitment-of-bone-marrow-derived-schwann-cells-implications-for-remyelination-therapy
#11
Sa Cai, Lei Han, Qiang Ao, Ying-Shing Chan, Daisy Kwok-Yan Shum
Strategies that exploit induced pluripotent stem cells (iPSCs) to derive neurons have relied on cocktails of cytokines and growth factors to bias cell-signaling events in the course of fate choice. These are often costly and inefficient, involving multiple steps. In this study, we took an alternative approach and selected 5 small-molecule inhibitors of key signaling pathways in an 8-day program to induce differentiation of human iPSCs into sensory neurons, reaching ≥80% yield in terms of marker proteins. Continuing culture in maintenance medium resulted in neuronal networks immunopositive for synaptic vesicle markers and vesicular glutamate transporters suggestive of excitatory neurotransmission...
February 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28190869/single-molecule-detection-thermal-fluctuation-and-life
#12
Toshio Yanagida, Yoshiharu Ishii
Single molecule detection has contributed to our understanding of the unique mechanisms of life. Unlike artificial man-made machines, biological molecular machines integrate thermal noises rather than avoid them. For example, single molecule detection has demonstrated that myosin motors undergo biased Brownian motion for stepwise movement and that single protein molecules spontaneously change their conformation, for switching to interactions with other proteins, in response to thermal fluctuation. Thus, molecular machines have flexibility and efficiency not seen in artificial machines...
2017: Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
https://www.readbyqxmd.com/read/28187350/conformational-selection-and-induced-fit-as-a-useful-framework-for-molecular-motor-mechanisms
#13
REVIEW
Eric A Galburt, Eric J Tomko
The linkage between macromolecular binding and conformational change that is ubiquitous in biological molecules can be understood in the context of the mechanisms of conformational selection and induced fit. Here, we explore mappings between these mechanisms of ligand binding and those underlying the translocation of molecular motors and the nucleic acid unwinding of helicases. The mechanism of biased motion exhibited by molecular motors is typically described as either a thermal ratchet or a power-stroke and nucleic acid helicases are characterized by either active or passive unwinding mechanisms...
February 3, 2017: Biophysical Chemistry
https://www.readbyqxmd.com/read/28186762/synthesis-and-pharmacological-characterization-of-novel-trans-cyclopropylmethyl-linked-bivalent-ligands-that-exhibit-selectivity-and-allosteric-pharmacology-at-the-dopamine-d3-receptor-d3r
#14
Vivek Kumar, Amy E Moritz, Thomas M Keck, Alessandro Bonifazi, Michael P Ellenberger, Christopher D Sibley, R Benjamin Free, Lei Shi, J Robert Lane, David R Sibley, Amy Hauck Newman
The development of bitopic ligands directed toward D2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28182413/targeting-bacillosamine-biosynthesis-in-bacterial-pathogens-development-of-inhibitors-to-a-bacterial-amino-sugar-acetyltransferase-from-campylobacter-jejuni
#15
Joris W De Schutter, James P Morrison, Michael James Morrison, Alessio Ciulli, Barbara Imperiali
The glycoproteins of selected microbial pathogens often include highly modified carbohydrates such as 2,4-diacetamidobacillosamine (diNAcBac). These glycoconjugates are involved in host cell interactions and may be associated with the virulence of medically-significant Gram-negative bacteria. In light of genetic studies demonstrating the attenuated virulence of bacterial strains in which modified carbohydrate biosynthesis enzymes have been knocked out, we are developing small molecule inhibitors of selected enzymes as tools to evaluate whether such compounds modulate virulence...
February 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28181498/arrestin-biased-at1r-agonism-induces-acute-catecholamine-secretion-through-trpc3-coupling
#16
Chun-Hua Liu, Zheng Gong, Zong-Lai Liang, Zhi-Xin Liu, Fan Yang, Yu-Jing Sun, Ming-Liang Ma, Yi-Jing Wang, Chao-Ran Ji, Yu-Hong Wang, Mei-Jie Wang, Fu-Ai Cui, Amy Lin, Wen-Shuai Zheng, Dong-Fang He, Chang-Xiu Qu, Peng Xiao, Chuan-Yong Liu, Alex R B Thomsen, Thomas Joseph Cahill, Alem W Kahsai, Fan Yi, Kun-Hong Xiao, Tian Xue, Zhuan Zhou, Xiao Yu, Jin-Peng Sun
Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signalling pathways. Here we reveal that TRV120027, a β-arrestin-1-biased agonist of the angiotensin II receptor type 1 (AT1R), stimulates acute catecholamine secretion through coupling with the transient receptor potential cation channel subfamily C 3 (TRPC3)...
February 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28181439/cryoem-structure-refinement-by-integrating-nmr-chemical-shifts-with-molecular-dynamics-simulations
#17
Juan R Perilla, Gongpu Zhao, Manman Lu, Jiying Ning, Guangjin Hou, In-Ja L Byeon, Angela M Gronenborn, Tatyana Polenova, Peijun Zhang
Single particle cryoEM has emerged as a powerful method for structure determination of proteins and complexes, complementing X-ray crystallography and NMR spectroscopy. Yet, for many systems, the resolution of cryoEM density map has been limited to 4-6 Å, which only allows for resolving bulky amino acids side chains, thus hindering accurate model building from the density map. On the other hand, experimental chemical shifts (CS) from solution and solid state MAS NMR spectra provide atomic level data for each amino acid within a molecule or a complex; however, structure determination of large complexes and assemblies based on NMR data alone remains challenging...
February 9, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28177311/polder-maps-improving-omit-maps-by-excluding-bulk-solvent
#18
Dorothee Liebschner, Pavel V Afonine, Nigel W Moriarty, Billy K Poon, Oleg V Sobolev, Thomas C Terwilliger, Paul D Adams
The crystallographic maps that are routinely used during the structure-solution workflow are almost always model-biased because model information is used for their calculation. As these maps are also used to validate the atomic models that result from model building and refinement, this constitutes an immediate problem: anything added to the model will manifest itself in the map and thus hinder the validation. OMIT maps are a common tool to verify the presence of atoms in the model. The simplest way to compute an OMIT map is to exclude the atoms in question from the structure, update the corresponding structure factors and compute a residual map...
February 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28169296/small-molecule-biased-formyl-peptide-receptor-agonist-compound-17b-protects-against-myocardial-ischaemia-reperfusion-injury-in-mice
#19
Cheng Xue Qin, Lauren T May, Renming Li, Nga Cao, Sarah Rosli, Minh Deo, Amy E Alexander, Duncan Horlock, Jane E Bourke, Yuan H Yang, Alastair G Stewart, David M Kaye, Xiao-Jun Du, Patrick M Sexton, Arthur Christopoulos, Xiao-Ming Gao, Rebecca H Ritchie
Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43...
February 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28167799/cell-population-structure-prior-to-bifurcation-predicts-efficiency-of-directed-differentiation-in-human-induced-pluripotent-cells
#20
Rhishikesh Bargaje, Kalliopi Trachana, Martin N Shelton, Christopher S McGinnis, Joseph X Zhou, Cora Chadick, Savannah Cook, Christopher Cavanaugh, Sui Huang, Leroy Hood
Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or "tipping point" at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
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