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      Development and simulation of fully glycosylated molecular models of ACE2-Fc fusion proteins and their interaction with the SARS-CoV-2 spike protein binding domain

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          Abstract

          We develop fully glycosylated computational models of ACE2-Fc fusion proteins which are promising targets for a COVID-19 therapeutic. These models are tested in their interaction with a fragment of the receptor-binding domain (RBD) of the Spike Protein S of the SARS-CoV-2 virus, via atomistic molecular dynamics simulations. We see that some ACE2 glycans interact with the S fragments, and glycans are influencing the conformation of the ACE2 receptor. Additionally, we optimize algorithms for protein glycosylation modelling in order to expedite future model development. All models and algorithms are openly available.

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          Most cited references35

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          A new coronavirus associated with human respiratory disease in China

          Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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            Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

            Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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              Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

              How SARS-CoV-2 binds to human cells Scientists are racing to learn the secrets of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan et al. present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. In the context of this complex, ACE2 is a dimer. A further structure shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures provide a basis for the development of therapeutics targeting this crucial interaction. Science, this issue p. 1444
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                Author and article information

                Contributors
                Role: InvestigationRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 August 2020
                2020
                5 August 2020
                : 15
                : 8
                : e0237295
                Affiliations
                [1 ] Chemical Engineering, UC Davis, Davis, CA, United States of America
                [2 ] Materials Science and Engineering, UC Davis, Davis, CA, United States of America
                [3 ] Global HealthShare Initiative, UC Davis, Davis, CA, United States of America
                CIC bioGUNE, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9946-3846
                Article
                PONE-D-20-13266
                10.1371/journal.pone.0237295
                7406073
                32756606
                8dde0902-cac8-4566-825c-29099b3413ab
                © 2020 Bernardi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 May 2020
                : 23 July 2020
                Page count
                Figures: 5, Tables: 1, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100007707, University of California, Davis;
                Award ID: COVID-19 Research Accelerator Funding Track
                BH, KAM, RF, and SN are partially supported by a CRAFT award (COVID-19 Research Accelerator Funding Track) by the University of California Davis ( https://covid19research.ucdavis.edu/tags/craft). YX was supported by NASA under grant or cooperative agreement award number NNX17AJ31G. KAM and SN were partially supported by NASA Space Technology Research (award number NNX17AJ31G) and by the Translational Research Institute through NASA (grant number NNX16AO69A). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Aeronautics and Space Administration (NASA) or the Translational Research Institute for Space Health (TRISH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Glycobiology
                Glycosylation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Glycosylation
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
                Viral pathogens
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Coronaviruses
                SARS coronavirus
                SARS CoV 2
                Biology and Life Sciences
                Biochemistry
                Biochemical Simulations
                Biology and Life Sciences
                Computational Biology
                Biochemical Simulations
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Viral Diseases
                Covid 19
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Interactions
                Biology and Life Sciences
                Molecular Biology
                Macromolecular Structure Analysis
                Protein Structure
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Structure
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Domains
                Biology and Life Sciences
                Cell Biology
                Cell Physiology
                Cell Binding
                Custom metadata
                Simulation data is added in Supplementary information and available for download on the datadryad.org website Analysis tool are available on github.
                COVID-19

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