1,720,959 research outputs found
Anthramycin-DNA binding explored by molecular simulations
No full textThe anticancer drug anthramycin inhibits replication and transcription processes by covalently binding to DNA. Here, we use molecular simulations to investigate the interaction between this ligand and the dodecanucleotide d[GCCAACGTTGGC]2. We start from the X-ray structure of the adduct anthramycin- d[CCAACGTTG*G]2, in which the drug binds covalently to guanine.1 We focus on the noncovalent complexes between the oligonucleotide and the anhydro and hydroxy forms of the drug. Molecular dynamics (MD) simulations show that only the hydroxy form lies in front of the reactive center for the whole simulation (∼20 ns), while the anhydro form moves inside the minor groove to the nearest base pair after ∼10 ns. This sliding process is associated to both energetic and structural relaxations of the complex. The accuracy of our computational setup is established by performing MD simulations of the covalent adduct and of a 14-mer complexed with anhydro-anthramycin. The MD simulations are complemented by hybrid Car-Parrinello quantum mechanics/molecular mechanics (QM/MM) simulations. These show that in the noncovalent complexes the electric field due to DNA polarizes the hydroxy and, even more, the anhydro form of the drug as to favor a nucleophilic attack by the alkylating guanine. This suggests that the binding process may be characterized by a multistep pathway, catalyzed by the electric field of DNA
Binding and Transport of Carboxylated Drugs by the Multidrug Transporter AcrB
Full text linkAcrAB(Z)-TolC is the main drug efflux transporter complex in Escherichia coli. The extrusion of various toxic compounds depends on several drug binding sites within the trimeric AcrB transporter. Membrane-localized carboxylated substrates, such as fusidic acid and hydrophobic β-lactams, access the pump via a groove between the transmembrane helices TM1 and TM2. In this article, the transport route from the initial TM1/TM2 groove binding site toward the deep binding pocket located in the periplasmic part has been addressed via molecular modeling studies followed by functional and structural characterization of several AcrB variants. We propose that membrane-embedded drugs bind initially to the TM1/TM2 groove, are oriented by the AcrB PN2 subdomain, and are subsequently transported via a PN2/PC1 interface pathway directly toward the deep binding pocket. Our work emphasizes the exploitation of multiple transport pathways by AcrB tuned to substrate physicochemical properties related to the polyspecificity of the pump
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
Copper-1,10-Phenanthroline Complexes Binding to DNA: Structural Predictions from Molecular Simulations
No full textCopper-1,10-phenanthroline (phen) complexes Cu(phen)2, Cu(2-Clip-phen), and Cu(3-Clip-phen) (Clip ) a serinol bridge between the phen parts) are typically employed as DNA-cleaving agents and are now becoming increasingly important for building multifunctional drugs with improved cytotoxic properties. For instance, Cu(3-Clip-phen) has been combined with distamycin-like minor-groove binders and cisplatin-derivatives, leading to promising results. Density Functional Theory (DFT) and docking calculations as well as molecular dynamics (MD) simulations were performed to describe the mode of binding to DNA of these complexes. Our data suggest the minor-groove binding to be more probable than (partial) intercalation and major-groove binding. In addition, it was found that a combination of factors including planarity, van der Waals interactions with DNA, and structural complementarities may be the key for the cleavage efficiency of these copper complexes
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
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