1,720,971 research outputs found
Computational investigation of function of membrane proteins : Amt/Rh Ammonium transporters and SecY translocon
Full text linkIn this thesis, we studied the function of the Amt/Rh family of proteins and of the SecY/Sec61 translocons using computational methods. The Amt/Rh proteins mediate transport of ammonium across the lipid bilayer. SecY and Sec61 translocons facilitate the insertion of membrane proteins or translocation of secreted proteins in prokaryotes and eukaryotes, respectively. We investigated on the molecular details of ammonium transport in E.Coli AmtB and human RhCG proteins, and the effect of the hydrophobicity of the SecY translocon pore in membrane protein insertion.
Functional studies have revealed that Amt proteins transport the charged form of ammonium (NH4+) while Rh proteins transport neutral ammonia (NH3). However, permeation mechanisms at a molecular level have not been understood clearly. Here, we present molecular details of ammonium transport in AmtB and RhCG proteins. Our calculations show that ammonium ion binds and deprotonates at the hydrophobic pore of AmtB. Then, ammonia diffuses down the hydrophobic pore while the excess proton is transported with the help of a highly conserved histidine dyad (H168 and H318). Ammonia gets re-protonated when it reaches the bottom of the pore and leaves the channel as ammonium. To recruit a new ammonium substrate the protonation states of the histidine dyad has to be reset. This is achieved through water molecules forming a single-file chain in the pore. Thus, hydration of the pore plays an important role in the transport mechanism in AmtB protein. Our simulations of RhCG protein have revealed that the pore of RhCG protein is not hydrated. Lack of hydration in the pore suggests that the excess proton cannot be transported across the hydrophobic pore as it is proposed for AmtB. We show that ammonium binds and deprotonates at a histidine residue (H185) lining the hydrophobic pore of RhCG. After deprotonation, ammonia diffuses down the pore. Then, the excess proton is circulated back to the extracellular site through a network of hydrogen bonds connecting H185 to D177. In conclusion, our calculations suggest that RhCG protein transports neutral ammonia while AmtB transports charged ammonium.
Experimental findings showed that mutation of the pore-ring residues of Sec61 translocon changed the hydrophobicity threshold for membrane integration. Our free energy calculations suggested that mutation of the pore-ring residues influences the stability of peptides in the pore, thus affecting the probability of membrane integration. In addition, insertion experiments of oligo alanine peptides, which contain a cluster of three leucines at various positions, revealed an asymmetry in the membrane integration profile. In particular, a significant drop in membrane integration was observed when the three-leucine cluster aligns with the pore-ring residues. We simulated the wild-type SecY and its pore-ring mutants with the oligo-alanine peptides initially placed into the pores. Analysis of these simulations suggested that hydration of the leucine side-chains drops dramatically when the three-leucine cluster is aligned with the pore-ring residues. The reduced hydration of the leucine residues stabilizes the peptide in the translocon pore and favors its translocation
Optimization of CHARMM force field parameters of a prostate cancer drug enzalutamide
No full textEnzalutamide is the most recent and potent clinically available drug molecule used to treat castration-resistant metastatic prostate cancer patients. In the presence of certain mutations on the Androgen receptor, enzalutamide fails to function as an antagonist. The molecular mechanism of this resistance has not been understood clearly. Molecular Dynamics (MD) simulations are a powerful tool to investigate such resistance mechanisms. Insights from MD simulations of receptor-ligand complex heavily depend on the quality of the parameters of the ligands. Thus, we developed and optimized CHARMM Force field parameters of enzalutamide. The initial assignment of parameters was done by using the CHARMM General Force Field (CGenFF) program. After that, using the Force Field Tool Kit (FFTK) partial charges, bond, angle and dihedral parameters of enzalutamide were optimized to reproduce quantum mechanics calculation results. For the validation of parameters, water-octanol partition coefficient, Infrared Spectra (IR) and normal mode analysis calculations were performed. In addition, a 300 ns-long MD simulation of enzalutamide was carried out to assess the ability of the optimized parameters in exploring torsional angle space. (C) 2020 Elsevier Inc. All rights reserved
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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