1,720,960 research outputs found
The role of time in biological systems: a computational analysis ranging from molecular dynamics to biological network simulations.
Get PDFTime is the main character of this thesis, and it has been used in many ways. Starting from molecular dynamics simulations to biological networks, time has been analysed under different light and roles. The main subjects characterizing this work are Von Hippel-Lindau syndrome and circadian rhythm, although a method for molecular dynamics simulations trajectory analysis is presented at the end. Several works are presented here, analysing different aspects of protein dynamics as well as pathway alterations depending on the time coordinate. The first work analyses the interaction between protein Von Hippel-Lindau (pVHL) and its main interactor, Hipoxya Inducibe Factor 1α by means of molecular dynamics simulations, investigating on a non-conventional proline hydroxylation event. As a result, we obtained that a specific hydrogen bond network rearrangement and improved electrostatic energy for hydroxylated P567 appear to be compatible with an increase in HIF-1α binding affinity. Sequence analysis also confirms P567 to be vastly conserved during evolution, indicating a possible role for this alternative, PHD-3 driven, post translational modification in pVHL–HIF-1α complex formation. The second work dealt with the same main subject, but investigated through biological network simulations, particularly with Petri net models. In this work, we presented a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways. In the third work, investigating the structural role of flavin-adenine-dinucleotide (FAD) through molecular dynamics simulations, we analyzed the Drosophila melanogaster Cryptochrome crystal structure, elucidating how this large co-factor within the receptor could be crucial for CRY structural stability. The co-factor appears indeed to improve receptor motility, providing steric hindrance. Moreover, multiple sequence alignments revealed that conserved motifs in the C-terminal tail could be necessary for functional stability. The fourth work focused on the sequence impact on the modern folds. We shuffled the sequences of 10 natural proteins and obtained 40 different and apparently unrelated folds. Our results suggest that shuffled sequences are sufficiently stable and may act as a basis to evolve functional proteins. The common secondary structure of modern proteins is well represented by a small set of permuted sequences, which also show the emergence of intrinsic disorder and aggregation-prone stretches of the polypeptide chain. The last work presented here is a method to quickly analyse molecular dynamics simulations trajectories. The complexity related to their interpretation and analysis is still one of the major challenges for most users. In this work we introduce RING MD, which is able to identify the most important frames (PDB structures) and key residues that cause different conformers transitions, providing a simple interpretation useful for non-expert users. Comparison with the classical analysis of three MD simulations, Ubiquitin, T4 Lysozyme and T4 Glutaredoxin, confirmed RING MD results and effectiveness.
At the end, time should not be considered simply as something entraining the environment, it is what indeed modifies systems and environment. Different systems simply change in different ways, because of different mechanisms, but the main driving force should always be considered time
Structural protein reorganization and fold emergence investigated through amino acid sequence permutations
No full textCorrelation between random amino acid sequences and protein folds suggests that proteins autonomously evolved the most stable folds, with stability and function evolving subsequently, suggesting the existence of common protein ancestors from which all modern proteins evolved. To test this hypothesis, we shuffled the sequences of 10 natural proteins and obtained 40 different and apparently unrelated folds. Our results suggest that shuffled sequences are sufficiently stable and may act as a basis to evolve functional proteins. The common secondary structure of modern proteins is well represented by a small set of permuted sequences, which also show the emergence of intrinsic disorder and aggregation-prone stretches of the polypeptide chain
In silico investigation of PHD-3 specific HIF1-α proline 567 hydroxylation: a new player in the VHL/HIF-1α interaction pathway?
No full textAbstractHypoxia inducible factor 1α (HIF-1α) regulates oxygen homeostasis in the cell through a sensing mechanism involving its hydroxylation and binding to the von Hippel–Lindau (VHL) tumor suppressor. This mechanism is mediated through hydroxylation of HIF-1α proline 564, although in vitro tests have previously shown an alternative hydroxylation at proline 567 by PHD-3. Here, molecular dynamics simulations were used to investigate the structural effect of this alternative hydroxylation. A specific hydrogen bond network rearrangement and improved electrostatic energy for hydroxylated P567 are compatible with an increase in HIF-1α binding affinity. Sequence analysis also confirms P567 to be vastly conserved during evolution, indicating a possible role for this alternative, PHD-3 driven, post translational modification in pVHL–HIF-1α complex formation
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
Evaluation of the steric impact of flavin adenine dinucleotide in Drosophila melanogaster cryptochrome function
No full textPhotoreceptors are crucial components for circadian rhythm entrainment in animals, plants, fungi and cyanobacteria. Cryptochromes (CRYs) are flavin adenine dinucleotide (FAD) containing photoreceptors, and FAD is responsible for signal transduction, in contrast to photolyases where it promotes DNA-damage repair. In this work, we investigated an alternative role for FAD in CRY. We analyzed the Drosophila melanogaster CRY crystal structure by means of molecular dynamics, elucidating how this large co-factor within the receptor could be crucial for CRY structural stability. The co-factor appears indeed to improve receptor motility, providing steric hindrance. Moreover, multiple sequence alignments revealed that conserved motifs in the C-terminal tail could be necessary for functional stability. (C) 2014 Elsevier Inc. All rights reserved
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