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Degiacomi M.T.,Ecole Polytechnique Federale de Lausanne | Degiacomi M.T.,Physical and Theoretical Chemistry Laboratory | Dal Peraro M.,Ecole Polytechnique Federale de Lausanne

Proteins often assemble in multimeric complexes to perform a specific biologic function. However, trapping these high-order conformations is difficult experimentally. Therefore, predicting how proteins assemble using in silico techniques can be of great help. The size of the associated conformational space and the fact that proteins are intrinsically flexible structures make this optimization problem extremely challenging. Nonetheless, known experimental spatial restraints can guide the search process, contributing to model biologically relevant states. We present here a swarm intelligence optimization protocol able to predict the arrangement of protein symmetric assemblies by exploiting a limited amount of experimental restraints and steric interactions. Importantly, within this scheme the native flexibility of each protein subunit is taken into account as extracted from molecular dynamics (MD) simulations. We show that this is a key ingredient for the prediction of biologically functional assemblies when, upon oligomerization, subunits explore activated states undergoing significant conformational changes. © 2013 Elsevier Ltd. Source

Wortham N.C.,University of Southampton | Martinez M.,University of Southampton | Gordiyenko Y.,Physical and Theoretical Chemistry Laboratory | Robinson C.V.,Physical and Theoretical Chemistry Laboratory | Proud C.G.,University of Southampton
FASEB Journal

Eukaryotic initiation factor 2B (eIF2B) is the guanine nucleotide exchange factor for eIF2 and a critical regulator of protein synthesis, (e.g., as part of the integrated stress response). Certain mutations in the EIF2B genes cause leukoencephalopathy with vanishing white matter (VWM), an often serious neurological disorder. Comprising 5 subunits, α-ε (eIF2Bε being the catalytic one), eIF2B has always been considered an αβγ δε heteropentamer. We have analyzed the subunit interactions within mammalian eIF2B by using a combination of mass spectrometry and in vivo studies of overexpressed complexes to gain further insight into the subunit arrangement of the complex. Our data reveal that eIF2B is actually decameric, a dimer of eIF2B(βγδε) tetramers stabilized by 2 copies of eIF2Bα.We also demonstrate a pivotal role for eIF2Bδ in the formation of eIF2B(βγδε) tetramers. eIF2B(αβ γδε)2 decamers show greater binding to eIF2 than to eIF2B(βγδε) tetramers, which may underlie the increased activity of the former. We examined the levels of eIF2B subunits in a panel of different mouse tissues and identified different levels of eIF2B subunits, particularly eIF2Bα, which implies heterogeneity in the cellular proportions of eIF2B(αβγδε) and eIF2B(βγ δε) complexes, with important implications for the regulation of translation in individual cell types. © FASEB. Source

Katelhon E.,Physical and Theoretical Chemistry Laboratory | Compton R.G.,Physical and Theoretical Chemistry Laboratory

The recent decade saw much interest in sensors based on nanoparticles. Such sensors typically employ sensing mechanisms that utilise the adsorption of analyte species on the nanoparticle surfaces, while adsorption induces changes in the physical properties of the nanoparticles. In this work, we introduce an analytical model for the rate of adsorption of analyte species on the nanoparticle surface. Expressions for the fractional surface coverage and the number of adsorbed molecules as a function of time are derived assuming spherical nanoparticles. Moreover, we provide values for common experimental conditions and show that for small nanoparticles (r < 10 nm) a surface coverages of 30% can be reached in less than 1 s at adsorbent concentrations as low as 50 nM. © the Partner Organisations 2014. Source

Toghill K.E.,Physical and Theoretical Chemistry Laboratory | Compton R.G.,Physical and Theoretical Chemistry Laboratory

Metal nanoparticle modified boron-doped diamond (BDD) electrodes have been used in the electroanalysis of a number of inorganic and organic analytes. This simple surface modification has enhanced the sensitivity and analytical ability of BDD effectively and consistently, as reported in a number of publications overviewed herein. In this review, a number of metal nanoparticle systems that have utilized BDD electrodes will be discussed. The low capacitance of BDD makes it an ideal substrate for sensitive dynamic electroanalytical experiments. The metal nanoparticle modification of BDD offers a simple yet effective approach to enhancing the electroanalytical ability of the electrode material. © 2010 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim. Source

Lu M.,Physical and Theoretical Chemistry Laboratory | Compton R.G.,Physical and Theoretical Chemistry Laboratory

A square wave voltammetric procedure for the determination of trace amounts of Fe(III) was developed at an unmodified edge plane pyrolytic graphite (EPPG) electrode and a screen printed electrode (SPE). This simple procedure was applied to real samples of commercially bottled mineral water. Sensitive results in the micromolar region could be achieved without modification of the electrode. Using the WHO guideline limits for the Fe(III) concentration in drinking water, recovery percentages at an EPPG gave 103% and 107%, and 98.6% and 95.0% at a SPE for the 5.36μM (0.3mgL-1) and 53.6μM (3.0mgL-1) additions of Fe(III), respectively. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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