1,720,959 research outputs found
Probing the transport of Ni(II) ions through the internal tunnels of the Helicobacter pylori UreDFG multimeric protein complex
No full textThe survival of several pathogenic bacteria, such as Helicobacter pylori (Hp), relies on the activity of the nickel dependent enzyme urease. Nickel insertion into urease is mediated by a multimeric chaperone complex (HpUreDFG) that is responsible for the transport of Ni(II) from a conserved metal binding motif located in the UreG dimer (CPH motif) to the catalytic site of the enzyme. The X-ray structure of HpUreDFG revealed the presence of water-filled tunnels that were proposed as a route for Ni(II) translocation. Here, we probe the transport of Ni(II) through the internal tunnels of HpUreDFG, from the CPH motif to the external surface of the complex, using microsecond-long enhanced molecular dynamics simulations. The results suggest a “bucketbrigade” mechanism whereby Ni(II) can be transported through a series of stations found along these internal pathways
Data-Driven Molecular Dynamics: A Multifaceted Challenge
Full text linkThe big data concept is currently revolutionizing several fields of science including drug discovery and development. While opening up new perspectives for better drug design and related strategies, big data analysis strongly challenges our current ability to manage and exploit an extraordinarily large and possibly diverse amount of information. The recent renewal of machine learning (ML)-based algorithms is key in providing the proper framework for addressing this issue. In this respect, the impact on the exploitation of molecular dynamics (MD) simulations, which have recently reached mainstream status in computational drug discovery, can be remarkable. Here, we review the recent progress in the use of ML methods coupled to biomolecular simulations with potentially relevant implications for drug design. Specifically, we show how different ML-based strategies can be applied to the outcome of MD simulations for gaining knowledge and enhancing sampling. Finally, we discuss how intrinsic limitations of MD in accurately modeling biomolecular systems can be alleviated by including information coming from experimental dat
Dynamic Docking: A Paradigm Shift in Computational Drug Discovery
Full text linkMolecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD) have emerged as a valid alternative for simulating macromolecular complexes. In principle, compared to traditional docking, MD allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic points of view (dynamic docking). Binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely used in fast-paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is feasible that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in in silico drug discovery. Against this background, we review the key achievements that have paved the way for this progress
Fully Flexible Docking via Reaction-Coordinate-Independent Molecular Dynamics Simulations
No full textPredicting the geometry of protein-ligand binding complexes is of primary importance for structure-based drug discovery. Molecular dynamics (MD) is emerging as a reliable computational tool for use in conjunction with, or an alternative to, docking methods. However, simulating the protein-ligand binding process often requires very expensive simulations. This drastically limits the practical application of MD-based approaches. Here, we propose a general framework to accelerate the generation of putative protein-ligand binding modes using potential-scaled MD simulations. The proposed dynamical protocol has been applied to two pharmaceutically relevant systems (GSK-3β and the N-terminal domain of HSP90α). Our approach is fully independent of any predefined reaction coordinate (or collective variable). It identified the correct binding mode of several ligands and can thus save valuable computational time in dynamic docking simulations
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
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