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      CHARMM-GUI Glycan Modeler for modeling and simulation of carbohydrates and glycoconjugates

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          Abstract

          Characterizing glycans and glycoconjugates in the context of three-dimensional structures is important in understanding their biological roles and developing efficient therapeutic agents. Computational modeling and molecular simulation have become an essential tool complementary to experimental methods. Here, we present a computational tool, Glycan Modeler for in silico N -/ O -glycosylation of the target protein and generation of carbohydrate-only systems. In our previous study, we developed Glycan Reader , a web-based tool for detecting carbohydrate molecules from a PDB structure and generation of simulation system and input files. As integrated into Glycan Reader in CHARMM-GUI, Glycan Modeler ( Glycan Reader & Modeler ) enables to generate the structures of glycans and glycoconjugates for given glycan sequences and glycosylation sites using PDB glycan template structures from Glycan Fragment Database ( http://glycanstructure.org/fragment-db ). Our benchmark tests demonstrate the universal applicability of Glycan Reader & Modeler to various glycan sequences and target proteins. We also investigated the structural properties of modeled glycan structures by running 2-μs molecular dynamics simulations of HIV envelope protein. The simulations show that the modeled glycan structures built by Glycan Reader & Modeler have the similar structural features compared to the ones solved by X-ray crystallography. We also describe the representative examples of glycoconjugate modeling with video demos to illustrate the practical applications of Glycan Reader & Modeler . Glycan Reader & Modeler is freely available at http://charmm-gui.org/input/glycan .

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          Most cited references 49

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          Trimeric HIV-1-Env Structures Define Glycan Shields from Clades A, B, and G.

          The HIV-1-envelope (Env) trimer is covered by a glycan shield of ∼90 N-linked oligosaccharides, which comprises roughly half its mass and is a key component of HIV evasion from humoral immunity. To understand how antibodies can overcome the barriers imposed by the glycan shield, we crystallized fully glycosylated Env trimers from clades A, B, and G, visualizing the shield at 3.4-3.7 Å resolution. These structures reveal the HIV-1-glycan shield to comprise a network of interlocking oligosaccharides, substantially ordered by glycan crowding, that encase the protein component of Env and enable HIV-1 to avoid most antibody-mediated neutralization. The revealed features delineate a taxonomy of N-linked glycan-glycan interactions. Crowded and dispersed glycans are differently ordered, conserved, processed, and recognized by antibody. The structures, along with glycan-array binding and molecular dynamics, reveal a diversity in oligosaccharide affinity and a requirement for accommodating glycans among known broadly neutralizing antibodies that target the glycan-shielded trimer.
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            Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation.

            The function of deciphering the biological information encoded by the glycome, which is the entire repertoire of complex sugar structures expressed by cells and tissues, is assigned in part to endogenous glycan-binding proteins or lectins. Galectins, a family of animal lectins that bind N-acetyllactosamine-containing glycans, have many roles in diverse immune cell processes, including those relevant to pathogen recognition, shaping the course of adaptive immune responses and fine-tuning the inflammatory response. How do galectins translate glycan-encoded information into tolerogenic or inflammatory cell programmes? An improved understanding of the mechanisms underlying these functions will provide further opportunities for developing new therapies based on the immunoregulatory properties of this multifaceted protein family.
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              Glycobiology: Toward Understanding the Function of Sugars.

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                Author and article information

                Contributors
                Journal
                Glycobiology
                Oxford University Press (OUP)
                1460-2423
                April 2019
                April 01 2019
                February 26 2019
                April 2019
                April 01 2019
                February 26 2019
                : 29
                : 4
                : 320-331
                Affiliations
                [1 ]Departments of Biological Sciences and Bioengineering, Lehigh University, Bethlehem, PA, USA
                [2 ]Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China
                [3 ]Leadership Computing Facility, Argonne National Laboratory, Argonne, IL, USA
                [4 ]Center for Advanced Computation, Korea Institute for Advanced Study, Republic of Korea
                Article
                10.1093/glycob/cwz003
                6422236
                30689864
                d615f135-9e19-4193-8bf3-3a8e62884795
                © 2019

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