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

PLoS One. 2020 Aug 5;15(8):e0237295. doi: 10.1371/journal.pone.0237295. eCollection 2020.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Angiotensin-Converting Enzyme 2
  • Betacoronavirus / isolation & purification
  • Betacoronavirus / metabolism*
  • Binding Sites
  • COVID-19
  • Coronavirus Infections / pathology
  • Coronavirus Infections / virology
  • Glycosylation
  • Humans
  • Molecular Dynamics Simulation*
  • Pandemics
  • Peptidyl-Dipeptidase A / chemistry*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / isolation & purification
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Recombinant Fusion Proteins
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Grants and funding

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.