1,721,045 research outputs found
Dynamical Treatment of Charge Transfer through Duplex Nucleic Acids Containing Modified Adenines
No full textProtein flexibility and ligand binding: dynamics of cellular retinol binding-protein types I and II
No full textRetinoids are essential for many physiological processes like cell growth and differentiation, morphogenesis, inmunocompetence and vision1. To exert their function they have to be transported to the appropriate site, but due to their low solubility they need to be transported by a group of proteins called Retinoid Binding Proteins (RBP). This is the case for all-trans retinol, the alcohol derivative of vitamin A that is transported from the liver to the epithelial tissue by the cellular retinol binding-protein isoform I (CRBP-I) and binds to the isoform II (CRBP-II) in the small intestin epithelial. The two isoforms share the ligand-binding motif and the structural superposition of apo and holo forms reveals no significant differences between them. However, CRBP-I binds retinol with approximately 100-fold higher affinity than CRBP-II.
NMR experiments indicate that amide protons exchange much faster in CRBP-II than in CRBP-I, thus isoform II should be more flexible than isoform I and that might explain the difference in affinity2,3. To tackle the problem from the computational view, we carried out a series of extended molecular dynamics simulations (3-5μs) of the two isoforms in their apo and holo states. The structural behavior of the systems is in agreement with the previous experimental results, as the key determinants of retinol affinity are related to the differential flexibility of the ligand portal site, specifically the ßE-ßF turn and helix α-II. Entropy analyses demonstrate the rigidification of the protein upon retinol binding. However, the differences in entropy found between apo and holo forms in CRBP-I are greater and more unfavorable in terms of binding than for CRBP-II. On the other hand, the different flexibility of both isoforms rises up a different hydration pattern of the binding site. Thus, CRBP-II exchanges water molecules with the bulk solvent more fluently than CRBP-I, and this process might play a significant role in the ligand binding/unbinding. Overall, the results indicate that the different affinity for retinol found in CRBP-I and CRBP-II results from a subtle interplay in the changes induced on protein dynamics and hydration by the ligand.
References
1. Blomhoff. R; Blomhoff, H. K. J.Neurobiol., 66, 606-630, 2006
2. Franzoni, L.; Lücke, C.; Perez, C.; Cavazzini, D.; Rademacher, M.; Ludwig, C.; Spisni, A.; Rossi, G. L.; Ruterjans, H. J. Biol. Chem., 277, 21983-21997, 2002
3. Franzoni, L.; Cavazzini, D.; Rossi, G. L.Lücke, C. J. Lip. Res, 51, 1332-1343. . 201
Application of the quantum mechanical IEF/PCM-MST hydrophobic descriptors to selectivity in ligand binding
No full textWe have recently reported the development and validation of quantum mechanical (QM)-based hydrophobic descriptors derived from the parametrized IEF/PCM-MST continuum solvation model for 3D-QSAR studies within the framework of the Hydrophobic Pharmacophore (HyPhar) method. In this study we explore the applicability of these descriptors to the analysis of selectivity fields. To this end, we have examined a series of 88 compounds with inhibitory activities against thrombin, trypsin and factor Xa, and the HyPhar results have been compared with 3D-QSAR models reported in the literature. The quantitative models obtained by combining the electrostatic and non-electrostatic components of the octanol/water partition coefficient yield results that compare well with the predictive potential of standard CoMFA and CoMSIA techniques. The results also highlight the potential of HyPhar descriptors to discriminate the selectivity of the compounds against thrombin, trypsin, and factor Xa. Moreover, the graphical representation of the hydrophobic maps provides a direct linkage with the pattern of interactions found in crystallographic structures. Overall, the results support the usefulness of the QM/MST-based hydrophobic descriptors as a complementary approach for disclosing structure-activity relationships in drug design and for gaining insight into the molecular determinants of ligand selectivity. Graphical Abstract Quantum Mechanical continuum solvation calculations performed with the IEF/PCM-MST method are used to derived atomic hydrophobic descriptors, which are then used to discriminate the selectivity of ligands against thrombin, trypsin and factor Xa. The descriptors provide complementary view to standard 3D-QSAR analysis, leading to a more comprehensive understanding of ligand recognition
From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus
Full text linkWith an estimated 1 billion people affected across the globe, influenza is one of the most serious health concerns worldwide. Therapeutic treatments have encompassed a number of key functional viral proteins, mainly focused on the M2 proton channel and neuraminidase. This review highlights the efforts spent in targeting the M2 proton channel, which mediates the proton transport toward the interior of the viral particle as a preliminary step leading to the release of the fusion peptide in hemagglutinin and the fusion of the viral and endosomal membranes. Besides the structural and mechanistic aspects of the M2 proton channel, attention is paid to the challenges posed by the development of efficient small molecule inhibitors and the evolution toward novel ligands and scaffolds motivated by the emergence of resistant strains
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
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