1,721,008 research outputs found
Ligand binding free energy and kinetics calculation in 2020
No full textLigand/protein binding (LPB) is a major topic in medicine, chemistry and biology. Since the advent of computers, many scientists have put efforts in developing theoretical models that could decode the alphabet of the LPB interaction. The success of this task passes by the resolution of the molecular mechanism of LPB. In the past century, major attention was dedicated to the thermodynamics of LPB, while more recent studies have revealed that ligand (un)binding kinetics is at least as important as ligand binding thermodynamics in determining the drug in vivo efficacy. In the present review, we introduce the most widely used computational methods to study LPB thermodynamics and kinetics. It is important to say that no method outperforms another, they all have pros and cons and the choice of the user should take carefully into account the system under investigation, the available structural and experimental data, and the goal of the research. A perspective on future directions of method development and research on LPB concludes the discussion. This article is categorized under: Molecular and Statistical Mechanics > Free Energy Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods
Ligand binding free-energy calculations with funnel metadynamics
No full textThe accurate resolution of the binding mechanism of a ligand to its molecular target is fundamental to develop a successful drug design campaign. Free-energy calculations, which provide the energy value of the ligand–protein binding complex, are essential for resolving the binding mode of the ligand. The accuracy of free-energy calculation methods is counteracted by their poor user-friendliness, which hampers their broad application. Here we present the Funnel-Metadynamics Advanced Protocol (FMAP), which is a flexible and user-friendly graphical user interface (GUI)-based protocol to perform funnel metadynamics, a binding free-energy method that employs a funnel-shape restraint potential to reveal the ligand binding mode and accurately calculate the absolute ligand–protein binding free energy. FMAP guides the user through all phases of the free-energy calculation process, from preparation of the input files, to production simulation, to analysis of the results. FMAP delivers the ligand binding mode and the absolute protein–ligand binding free energy as outputs. Alternative binding modes and the role of waters are also elucidated, providing a detailed description of the ligand binding mechanism. The entire protocol on the paradigmatic system benzamidine–trypsin, composed of ~105 k atoms, took ~2.8 d using the Cray XC50 piz Daint cluster at the Swiss National Supercomputing Centre
Modeling of Cdc25B dual specifity protein phosphatase inhibitors: Docking of ligands and enzymatic inhibition mechanism
No full textThe Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA
Minute-timescale free-energy calculations reveal a pseudo-active state in the adenosine A2A receptor activation mechanism
Full text linkG protein-coupled receptors (GPCRs) are membrane proteins targeted by over one-third of marketed drugs. Understanding their activation mechanism is essential for precise regulation of drug pharmacological response. In this work, we elucidate the conformational landscape of the adenosine A2A receptor (A2AR) activation mechanism in its basal apo form and under different ligand-bound conditions through minute-timescale free-energy calculations. We identified a pseudo-active state (pAs) of the A2AR apo form, stabilized by specific “microswitch” residues, including a salt bridge established between the conserved residues R5.66 and E6.30. The pAs enables A2AR to couple with Gs protein upon rearrangement of the intracellular end of transmembrane helix 6, providing unprecedented structural insights into receptor function and signaling dynamics. Our simulation protocol is versatile and can be adapted to study the activation of any GPCRs, potentially making it a valuable tool for drug design and “biased signaling” studies
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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