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molecular dynamics

Akash Kumar Singh, Sarmistha Halder Sinha, James P Clement, Tapas K Kundu
The accumulation of somatic and genetic mutations which altered the structure and coding information of the DNA are the major cause of neurological disorders. However, our recent understanding of molecular mechanisms of 'epigenetic' phenomenon reveals that the modifications of chromatin play a significant role in the development and severity of neurological disorders. These epigenetic processes are dynamic and reversible as compared to genetic ablations which are stable and irreversible. Therefore, targeting these epigenetic processes through small molecule modulators are of great therapeutic potential...
April 20, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Gennady M Verkhivker
Allosteric interactions of the Hsp90 chaperones with cochaperones and diverse protein clients can often exhibit distinct asymmetric features that determine regulatory mechanisms and cellular functions in many signaling networks. The recent crystal structures of the mitochondrial Hsp90 isoform TRAP1 in complexes with ATP analogs have provided first evidence of significant asymmetry in the closed dimerized state that triggers independent activity of the chaperone protomers, whereby preferential hydrolysis of the buckled protomer is followed by conformational flipping between protomers and hydrolysis of the second protomer...
April 20, 2018: Biochimica et Biophysica Acta
Julie Jézéquel, Julien P Dupuis, François Maingret, Laurent Groc
BACKGROUND: Over the past decade, an increasing number of neurological and neuropsychiatric diseases have been associated with the expression of autoantibodies directed against neuronal targets, including neurotransmitter receptors. Although cell-based assays are routinely used in clinics to detect the presence of immunoglobulins, such tests often provide heterogeneous outcomes due to their limited sensitivity, especially at low titers. Thus, there is an urging need for new methods allowing the detection of autoantibodies in seropositive patients that cannot always be clinically distinguished from seronegative ones...
April 20, 2018: Journal of Neuroscience Methods
David St-Pierre, Jérôme Cabana, Brian J Holleran, Élie Besserer-Offroy, Emanuel Escher, Gaétan Guillemette, Pierre Lavigne, Richard Leduc
G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures...
April 20, 2018: Biochemical Pharmacology
Franca Rossi, Castrese Morrone, Alberto Massarotti, Davide Maria Ferraris, Anna Valenti, Giuseppe Perugino, Riccardo Miggiano
The self-labeling protein tags are robust and versatile tools for studying different molecular aspects of cell biology. In order to be suitable for a wide spectrum of experimental conditions, it is mandatory that these systems are stable after the fluorescent labeling reaction and do not alter the properties of the fusion partner. SsOGT-H5 is an engineered variant alkylguanine-DNA-alkyl-transferase (OGT) of the hyperthermophilic archaeon Sulfolobus solfataricus, and it represents an alternative solution to the SNAP-tag® technology under harsh reaction conditions...
April 20, 2018: Biochemical and Biophysical Research Communications
Jasmine M Gardner, Cameron F Abrams
Molecular dynamics simulations of a solvent-free coarse-grained lipid model are used to characterize the mechanisms by which lipid-bilayer hemifusion diaphragm (HD) intermediates relax, across a range of global compositions of negative intrinsic curvature (NIC) lipids and neutral-curvature lipids. At low concentrations of NIC lipids, rapid fission produces a double bilayer end state through a lateral diffusion-based mechanism enabled by spontaneous rim-pore defects. At moderately higher NIC lipid concentrations, rim pores are absent and stable leaflet three-junctions persist, revealing an HD relaxation mechanism entirely reliant on lipid flip-flop, and end states that are either stable fusion pores or stable HD's...
April 20, 2018: Biochimica et Biophysica Acta
Ezequiel N Frigini, J J López Cascales, Rodolfo D Porasso
Extensive Molecular Dynamics simulations have been performed to study the effect of Glyphosate (in their neutral and charged forms, GLYP and GLYP2- , respectively) on fully hydrated DiPalmitoylPhosphatidylCholine (DPPC) lipid bilayer. First, we calculated the free energy profile (using the Umbrella Sampling technique) for both states of charge of glyphosate. The minimum value for the free energy for GLYP is ∼-60 kJ.mol-1 located at z=±1.7 nm (from the lipid bilayer center), and there is almost no maximum at the center of the lipid bilayer...
April 20, 2018: Chemistry and Physics of Lipids
Patricia Mingo-Casas, Virginia Sandonís, Elena Obón, José M Berciano, Sonia Vázquez-Morón, Javier Juste, Juan E Echevarría
Previous studies have shown that EBLV-1 strains exclusively hosted by Eptesicus isabellinus bats in the Iberian Peninsula cluster in a specific monophyletic group that is related to the EBLV-1b lineage found in the rest of Europe. More recently, enhanced passive surveillance has allowed the detection of the first EBLV-1 strains associated to Eptesicus serotinus south of the Pyrenees. The aim of this study is the reconstruction of the EBLV-1 phylogeny and phylodynamics in the Iberian Peninsula in the context of the European continent...
April 23, 2018: PLoS Neglected Tropical Diseases
Carl D Britto, Zoe A Dyson, Sebastian Duchene, Michael J Carter, Meeru Gurung, Dominic F Kelly, David R Murdoch, Imran Ansari, Stephen Thorson, Shrijana Shrestha, Neelam Adhikari, Gordon Dougan, Kathryn E Holt, Andrew J Pollard
BACKGROUND: Children are substantially affected by enteric fever in most settings with a high burden of the disease, including Nepal. However pathogen population structure and transmission dynamics are poorly delineated in young children, the proposed target group for immunization programs. Here we present whole genome sequencing and antimicrobial susceptibility data on 198 S. Typhi and 66 S. Paratyphi A isolated from children aged 2 months to 15 years of age during blood culture surveillance at Patan Hospital, Nepal, 2008-2016...
April 23, 2018: PLoS Neglected Tropical Diseases
UnCheol Lee, George A Mashour
The heterogeneity of molecular mechanisms, target neural circuits, and neurophysiologic effects of general anesthetics makes it difficult to develop a reliable and drug-invariant index of general anesthesia. No single brain region or mechanism has been identified as the neural correlate of consciousness, suggesting that consciousness might emerge through complex interactions of spatially and temporally distributed brain functions. The goal of this review article is to introduce the basic concepts of networks and explain why the application of network science to general anesthesia could be a pathway to discover a fundamental mechanism of anesthetic-induced unconsciousness...
April 23, 2018: Anesthesiology
Carolyn Vargas, Christian Schönbeck, Ina Heimann, Sandro Keller
Cyclodextrin (CD) complexation is a convenient method to sequester surfactants in a controllable way, for example, during membrane-protein reconstitution. Interestingly, the equilibrium stability of CD/surfactant inclusion complexes increases with the length of the nonpolar surfactant chain even beyond the point where all hydrophobic contacts within the canonical CD cavity are saturated. To rationalize this observation, we have dissected the inclusion complexation equilibria of a structurally well-defined CD, that is, heptakis(2,6-di-O methyl)-CD (DIMEB), and a homologous series of surfactants, namely, n alkyl-N,N dimethyl-3 ammonio-1 propanesulfonates (SB3 x) with chain lengths ranging from x = 8 to 14...
April 23, 2018: Langmuir: the ACS Journal of Surfaces and Colloids
Max A Mattson, Thomas D Green, Peter T Lake, Martin McCullagh, Amber T Krummel
Perylene diimides (PDI) are a family of molecules that have potential applications to organic photovoltaics. These systems typically aggregate cofacially due to π-stacking interactions between the aromatic perylene cores. In this study, the structure and characteristics of aggregated N,N'-bis(2,6-diisopropylphenyl)-3,4,9,10-perylenetetracarboxylic diimide (common name lumogen orange), a perylene diimide (PDI) with sterically bulky imide functional groups were investigated using both experimental vibrational spectroscopy and molecular dynamics (MD) simulations...
April 23, 2018: Journal of Physical Chemistry. B
Claas Strecker, Bernd Meyer
Protein flexibility poses a major challenge to docking of potential ligands in that the binding site can adopt different shapes. Docking algorithms usually keep the protein rigid and only allow the ligand to be treated as flexible. However, a wrong assessment of the shape of the binding pocket can prevent a ligand from adapting a correct pose. Ensemble docking is a simple yet promising method to solve this problem: Ligands are docked into multiple structures and the results are subsequently merged. Selection of protein structures is a significant factor for this approach...
April 23, 2018: Journal of Chemical Information and Modeling
Ryan A Folk, Pamela S Soltis, Douglas E Soltis, Robert Guralnick
Assessing the relative importance of the various pathways to diversification is a central goal of biodiversity researchers. For plant biologists, and increasingly across the spectrum of biological sciences, among these pathways of interest is hybridization. New methodological developments are moving the field away from questions of whether natural hybridization occurs or hybrids can persist and toward more direct assessments of the long-term impact of hybridization on diversification and genome organization...
February 14, 2018: American Journal of Botany
Antoine Creugny, Aurélie Fender, Sébastien Pfeffer
MicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the fine-tuning of many, if not all, fundamental biological processes. Molecular mechanisms involved in miRNA biogenesis and mode of action have been elucidated in the past two decades. Similar to many cellular pathways, miRNA processing and function can be globally or specifically regulated at several levels and by numerous proteins and RNAs. Given their role as fine-tuning molecules, it is essential for miRNA expression to be tightly regulated in order to maintain cellular homeostasis...
April 23, 2018: FEBS Letters
Taj Mohammad, Faez Iqbal Khan, Kevin A Lobb, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected based on the binding affinities, docking scores and selectivity...
April 23, 2018: Journal of Biomolecular Structure & Dynamics
Yu D Gordievskaya, Yu A Budkov, E Yu Kramarenko
The effect of an interplay between electrostatic and excluded volume interactions on the conformational behavior of a dipolar chain has been studied theoretically and by means of molecular dynamics simulations. Every monomer unit of the dipolar chain comprises a dipole formed by a charged group of the chain and an oppositely charged counterion. The counterion is assumed to freely move around the chain but keeping the distance between oppositely charged ions (the dipole length) fixed. The novelty of the developed mean-field theory is that variations of the dipole parameters (the dipole length and the counterion size) have been accounted for in both electrostatic and excluded volume contributions to the total free energy of the dipolar chain...
April 23, 2018: Soft Matter
Zhilin Yang, Junxian Chen, Yang Zhou, Hui Huang, Dingguo Xu, Chaoyang Zhang
The explosive 2,4,6-trinitrotoluene (TNT) is a highly toxic pollutant. Biodegradation is inevitably one of the most cost-effective and enviromentally friendly means of removing TNT pollution. However, the aromatic derivatives from the reduction of nitro groups by several classic enzymes are still toxic. Besides the reduction of nitro groups, pentaerythritol tetranitrate reductase (PETNR) offers a potential route to ring fission and complete degradation of TNT through the pathway of the Meisenheimer complex...
April 23, 2018: Physical Chemistry Chemical Physics: PCCP
F J Valencia, E E Hernandez-Vazquez, E M Bringa, J L Moran-Lopez, J Rogan, R I Gonzalez, F Munoz
We studied the soft landing of Ni atoms on a previously damaged graphene sheet by means of molecular dynamics simulations. We found a monotonic decrease of the cluster frequency as a function of its size, but few big clusters comprise an appreciable fraction of the total number of Ni atoms. The aggregation of Ni atoms is also modeled by means of a simple phenomenological model. The results are in clear contrast with the case of hard or energetic landing of metal atoms, where there is a tendency to form mono-disperse metal clusters...
April 23, 2018: Physical Chemistry Chemical Physics: PCCP
Ádria P B Saraiva, Ricardo M Miranda, Renan P P Valente, Jéssica O Araújo, Rutelene N B Souza, Clauber H S Costa, Amanda R S Oliveira, Michell O Almeida, Antonio F Figueiredo, João E V Ferreira, Cláudio Nahum Alves, Kathia M Honorio
In this work a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q2 and r2 ) for the models were, respectively, 0...
April 22, 2018: Chemical Biology & Drug Design
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