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91.
We apply the Blue Moon constrained Molecular Dynamics technique to study a particular case of molecular recognition, one of the main issues of modern molecular biology. We investigate the effects of mutation of interface residues on the binding strength of the dimeric protein superoxide dismutase from Photobacterium leiognathi. With our technique we produce a specific path describing the separation of the dimers and we calculate the effective mean force involved in the process. We apply the method to two mutants and compare the results with those obtained in an earlier calculation on the native enzyme. The method is sensitive to the mutations and allows us to establish a semi-quantitative hierarchy for the association strengths of the three enzymes. 相似文献
92.
The "Blue Moon" ensemble is a computationally efficient molecular dynamics method to estimate the rate constants of rare activated events when the process can be described by a reaction coordinate ξ(r), a well-defined function in configuration space. By means of holonomic constraints a number of values of ξ(r) can be prescribed along the relevant path to identify the "bottleneck" region first and to sample an ensemble of starting conditions to generate activated trajectories. These MD trajectories sample phase space according to a biased configurational distribution. With a suitable re-weighting of averages from such ensemble of trajectories one can characterize completely rare events. 相似文献
93.
Robert K.-Z. Tan Stephen C. Harvey Ernesto Di Mauro Giorgio Camilloni Patrizia Venditti 《Journal of biomolecular structure & dynamics》2013,31(5):855-872
Abstract We have analyzed the reactivity of a 217 base pair segment of the intrinsically curved Crithidia fasciculata kinetoplast DNA towards eukaryotic DNA topoisomerase I. The substrates were open [linear fragment and nicked circle] and closed minidomains [closed relaxed circle and circles with linking differences of ?1 and ?2], We interpreted the results with the aid of a model that was used to predict the structures of the topoisomers. The modelling shows that the ΔLk(?l) form is unusually compact because of the curvature in the DNA. To determine the role of sequence-directed curvature in both the experimental and modeling studies, controls were examined in which the curved Crithidia sequence was replaced by an uncurved sequence obtained from the plasmid pBR322. Reactivity of the Crithidia DNA [as analyzed both by the cleavage and the topoisomerization reactions] markedly varied among the DNA forms: (i) the hierarchy of overall reactivity observed is: linear fragment > nicked circular, closed circular [ΔLk(O)], interwound [ΔLk(?2)] > bent interwound [ΔLk(?l)]; (ii) the intensity of several cleavage positions differs among DNA forms. The results show that eukaryotic DNA topoisomerase I is very sensitive to the conformation of the substrates and that its reactivity is modulated by the variation of the compactness of the DNA molecule. The C. fasciculata sequence contains a highly curved segment that determines the conformation of the closed circle in a complex way. 相似文献
94.
95.
Eric E. Irons Justin W. Flatt Konstantin Doronin Tara L. Fox Mauro Acchione Phoebe L. Stewart Dmitry M. Shayakhmetov 《Journal of virology》2013,87(17):9610-9619
Adenoviruses (Ads) are promising vectors for therapeutic interventions in humans. When injected into the bloodstream, Ad vectors can bind several vitamin K-dependent blood coagulation factors, which contributes to virus sequestration in the liver by facilitating transduction of hepatocytes. Although both coagulation factors FVII and FX bind the hexon protein of human Ad serotype 5 (HAdv5) with a very high affinity, only FX appears to play a role in mediating Ad-hepatocyte transduction in vivo. To understand the discrepancy between efficacy of FVII binding to hexon and its apparently poor capacity for supporting virus cell entry, we analyzed the HAdv5-FVII complex by using high-resolution cryo-electron microscopy (cryo-EM) followed by molecular dynamic flexible fitting (MDFF) simulations. The results indicate that although hexon amino acids T423, E424, and T425, identified earlier as critical for FX binding, are also involved in mediating binding of FVII, the FVII GLA domain sits within the surface-exposed hexon trimer depression in a different orientation from that found for FX. Furthermore, we found that when bound to hexon, two proximal FVII molecules interact via their serine protease (SP) domains and bury potential heparan sulfate proteoglycan (HSPG) receptor binding residues within the dimer interface. In contrast, earlier cryo-EM studies of the Ad-FX interaction showed no evidence of dimer formation. Dimerization of FVII bound to Ad may be a contributing mechanistic factor for the differential infectivity of Ad-FX and Ad-FVII complexes, despite high-affinity binding of both these coagulation factors to the virus. 相似文献
96.
Mauro I. Schiaffini Magalí Gabrielli Francisco J. Prevosti Yamila P. Cardoso Diego Castillo Roberto Bo Emma Casanave Marta Lizarralde 《Zoological Journal of the Linnean Society》2013,167(2):327-344
Despite recent taxonomic evaluations of Mephitidae and North American hog‐nosed skunks, southern South American species of Conepatus have not been thoroughly examined in a systematic context. Conepatus chinga and Conepatus humboldtii were described more than 150 years ago, based on external characters such as hair coloration and size. Although historically recognized as valid species, to date no detailed systematic analysis has been performed for either of these taxa. Herein, we evaluated the taxonomic status of C. chinga and C. humboldtii within the southern part of South America using geometric morphometrics of the skull and mandible, mitochondrial DNA analysis using the cytochrome b and cytochrome oxidase c subunit I genes, and also control region and pelage pattern variation. We failed to find morphological (skull shape and pelage coloration patterns) or molecular differences between these two species; thus, we considered that the specimens assigned to C. chinga and C. humboldtii belong to the same species. Our results indicate that environmental variation seems to be responsible for shape and size variation in Conepatus skulls from southern South America. © 2013 The Linnean Society of London 相似文献
97.
Sonia Eligini Mauro Crisci Elisa Bono Paola Songia Elena Tremoli Gualtiero I. Colombo Susanna Colli 《Journal of cellular physiology》2013,228(7):1464-1472
Tissue macrophages are resident phagocytes that acquire specific phenotypes according to the microenvironment. Morphological and functional heterogeneity has been evidenced in different homeostatic and pathological conditions. Indeed, the nature of macrophage subsets may have either harmful or beneficial functions in disease progression/resolution. Therefore the possibility to pharmacologically manipulate heterogeneity represents a relevant challenge. Since human tissue macrophages are not easily obtained, various in vitro models are currently used that do not adequately reflect the heterogeneity and plasticity of tissue macrophages. We had previously reported that two dominant and distinct macrophage morphotypes co‐exist in the same culture of human monocytes spontaneously differentiated for 7 days in autologous serum. The present study was aimed to the phenotypic characterization of these morphotypes, that is, round‐ and spindle‐shaped. We observed that, besides substantial differences in cytoskeleton architecture, round monocyte‐derived macrophages (MDMs) showed higher lipid content, increased macropinocytosis/efferocytosis capacity, and overexpression of CD163, interleukin (IL)‐10, and transforming growth factor (TGF) β2. Conversely, spindle MDMs exhibited enhanced respiratory burst and higher expression of the chemokine (C‐C motif) ligands 18 and 24 (CCL18 and CCL24). Overall, round MDMs show functional traits reminiscent of the non‐inflammatory and reparative M2 phenotype, whereas spindle MDMs exhibit a pro‐inflammatory profile and express genes driving lymphocyte activation and eosinophil recruitment. MDMs obtained in the culture condition herein described represent a valuable model to disentangle and manipulate the functional heterogeneity of tissue macrophages that has been disclosed in scenarios spanning from inflammatory and wounding responses to atherosclerotic lesions. J. Cell. Physiol. 228: 1464–1472, 2013. © 2012 Wiley Periodicals, Inc. 相似文献
98.
Rosane Dias Costa Vanessa Amaral Mendon?a Frederico Marianetti Soriani Sandra Lyon Rachel Adriana Penido Ana Maria Duarte Dias Costa Marina Dias Costa Fabio de Souza Terra Mauro Martins Teixeira Carlos Mauricio de Figueiredo Antunes Antonio Lúcio Teixeira 《Memórias do Instituto Oswaldo Cruz》2013,108(8):1051-1056
Leprosy is an infectious and contagious spectral disease accompanied by a series of
immunological events triggered by the host response to the aetiologic agent,
Mycobacterium leprae . The induction and maintenance of the
immune/inflammatory response in leprosy are linked to multiple cell interactions and
soluble factors, primarily through the action of cytokines. The purpose of the
present study was to evaluate the serum levels of tumour necrosis factor (TNF)-α and
its soluble receptors (sTNF-R1 and sTNF-R2) in leprosy patients at different stages
of multidrug treatment (MDT) in comparison with non-infected individuals and to
determine their role as putative biomarkers of the severity of leprosy or the
treatment response. ELISA was used to measure the levels of these molecules in 30
healthy controls and 37 leprosy patients at the time of diagnosis and during and
after MDT. Our results showed increases in the serum levels of TNF-α and sTNF-R2 in
infected individuals in comparison with controls. The levels of TNF-α, but not
sTNF-R2, decreased with treatment. The current results corroborate previous reports
of elevated serum levels of TNF-α in leprosy and suggest a role for sTNF-R2 in the
control of this cytokine during MDT. 相似文献
99.
Capsule We report on the courtship behaviour of the Eurasian Bittern from direct observation in rice fields. 相似文献
100.