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      Agonist Binding to Chemosensory Receptors: A Systematic Bioinformatics Analysis

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          Abstract

          Human G-protein coupled receptors (hGPCRs) constitute a large and highly pharmaceutically relevant membrane receptor superfamily. About half of the hGPCRs' family members are chemosensory receptors, involved in bitter taste and olfaction, along with a variety of other physiological processes. Hence these receptors constitute promising targets for pharmaceutical intervention. Molecular modeling has been so far the most important tool to get insights on agonist binding and receptor activation. Here we investigate both aspects by bioinformatics-based predictions across all bitter taste and odorant receptors for which site-directed mutagenesis data are available. First, we observe that state-of-the-art homology modeling combined with previously used docking procedures turned out to reproduce only a limited fraction of ligand/receptor interactions inferred by experiments. This is most probably caused by the low sequence identity with available structural templates, which limits the accuracy of the protein model and in particular of the side-chains' orientations. Methods which transcend the limited sampling of the conformational space of docking may improve the predictions. As an example corroborating this, we review here multi-scale simulations from our lab and show that, for the three complexes studied so far, they significantly enhance the predictive power of the computational approach. Second, our bioinformatics analysis provides support to previous claims that several residues, including those at positions 1.50, 2.50, and 7.52, are involved in receptor activation.

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          Most cited references188

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          UCSF Chimera--a visualization system for exploratory research and analysis.

          The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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            AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

            AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.
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              The Pfam protein families database.

              Pfam is a large collection of protein families and domains. Over the past 2 years the number of families in Pfam has doubled and now stands at 6190 (version 10.0). Methodology improvements for searching the Pfam collection locally as well as via the web are described. Other recent innovations include modelling of discontinuous domains allowing Pfam domain definitions to be closer to those found in structure databases. Pfam is available on the web in the UK (http://www.sanger.ac.uk/Software/Pfam/), the USA (http://pfam.wustl.edu/), France (http://pfam.jouy.inra.fr/) and Sweden (http://Pfam.cgb.ki.se/).
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                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                06 September 2017
                2017
                : 4
                : 63
                Affiliations
                [1] 1Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich Jülich, Germany
                [2] 2Department of Biotechnology, University of Verona Verona, Italy
                [3] 3Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf Düsseldorf, Germany
                [4] 4Institute of Neuroscience and Medicine INM-1, Forschungszentrum Jülich Jülich, Germany
                [5] 5Institute for Human Genetics, Department of Genomics, Life&Brain Center, University of Bonn Bonn, Germany
                [6] 6Division of Medical Genetics, Department of Biomedicine, University of Basel Basel, Switzerland
                [7] 7Department of Physics, Rheinisch-Westfälische Technische Hochschule Aachen Aachen, Germany
                [8] 8VNU Key Laboratory “Multiscale Simulation of Complex Systems”, VNU University of Science, Vietnam National University Hanoi, Vietnam
                Author notes

                Edited by: Piero Andrea Temussi, University of Naples Federico II, Italy

                Reviewed by: Alfonso De Simone, Imperial College London, United Kingdom; Christopher Cooper, University of Huddersfield, United Kingdom

                *Correspondence: Mercedes Alfonso-Prieto m.alfonso-prieto@ 123456fz-juelich.de

                This article was submitted to Structural Biology, a section of the journal Frontiers in Molecular Biosciences

                †These authors have contributed equally to this work.

                Article
                10.3389/fmolb.2017.00063
                5592726
                28932739
                9cd990a5-2b0c-4e60-a05f-ce6ba5a004d4
                Copyright © 2017 Fierro, Suku, Alfonso-Prieto, Giorgetti, Cichon and Carloni.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 June 2017
                : 22 August 2017
                Page count
                Figures: 2, Tables: 4, Equations: 3, References: 180, Pages: 14, Words: 12795
                Categories
                Molecular Biosciences
                Original Research

                g-protein coupled receptor,chemosensory receptor,bitter taste receptor,odorant receptor,bioinformatics,homology modeling,molecular docking,molecular mechanics/coarse grained simulations

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