SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.
Abstract
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.
Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Calvin University, Grand Rapids, Michigan, USA.Department of Mathematics, University of North Alabama, Florence, Alabama, USA.Department of Mathematics, University of North Alabama, Florence, Alabama, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Grand Rapids Community College, Grand Rapids, Michigan, USA.Grand Rapids Community College, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Walsh University, North Canton, Ohio, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. Walsh University, North Canton, Ohio, USA.Walsh University, North Canton, Ohio, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.Department of Critical Care Medicine and Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.Spectrum Health Medical Genetics, Grand Rapids, Michigan, USA.Department of Physiology, Michigan State University, East Lansing, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA. Pediatric Intensive Care Unit, Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA. Office of Research, Spectrum Health, Grand Rapids, Michigan, USA.Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA jprokop54@gmail.com. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA. MeSH
African Continental Ancestry GroupAmino Acid Transport Systems, NeutralAngiotensin-Converting Enzyme 2BetacoronavirusCOVID-19Coronavirus InfectionsCoronavirus Nucleocapsid ProteinsDatabases, ProteinGenetic Predisposition to DiseaseGenetic VariationHost-Pathogen InteractionsHumansMaleMolecular Dynamics SimulationNucleocapsid ProteinsPandemicsPeptidyl-Dipeptidase APhosphoproteinsPneumonia, ViralProtein Interaction MapsProtein Processing, Post-TranslationalProteomeSARS-CoV-2Sequence Homology, Amino AcidSerine EndopeptidasesSpike Glycoprotein, Coronavirus
Pub Type(s)
Journal Article
Research Support, N.I.H., Extramural
