SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics
SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics
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.
- University of Pittsburgh United States
- Spectrum Health United States
- Helen DeVos Children's Hospital United States
- Michigan State University United States
- University of North Alabama United States
Male, RNA virus, post-translational modification (PTM), 572, Genomics and Proteomics, Pneumonia, Viral, human genetics, Black People, 612, virus entry, Molecular Dynamics Simulation, Peptidyl-Dipeptidase A, Biochemistry, Betacoronavirus, receptor structure-function, Coronavirus Nucleocapsid Proteins, Humans, Genetic Predisposition to Disease, Protein Interaction Maps, protein structure, Databases, Protein, Molecular Biology, Pandemics, molecular evolution, COVID-19, Genetic Variation, Cell Biology, Nucleocapsid Proteins, Phosphoproteins, molecular dynamics, severe acute respiratory coronavirus 2 (SARS-CoV-2), Amino Acid Transport Systems, Neutral, Host-Pathogen Interactions, Angiotensin-Converting Enzyme 2, Coronavirus Infections
Male, RNA virus, post-translational modification (PTM), 572, Genomics and Proteomics, Pneumonia, Viral, human genetics, Black People, 612, virus entry, Molecular Dynamics Simulation, Peptidyl-Dipeptidase A, Biochemistry, Betacoronavirus, receptor structure-function, Coronavirus Nucleocapsid Proteins, Humans, Genetic Predisposition to Disease, Protein Interaction Maps, protein structure, Databases, Protein, Molecular Biology, Pandemics, molecular evolution, COVID-19, Genetic Variation, Cell Biology, Nucleocapsid Proteins, Phosphoproteins, molecular dynamics, severe acute respiratory coronavirus 2 (SARS-CoV-2), Amino Acid Transport Systems, Neutral, Host-Pathogen Interactions, Angiotensin-Converting Enzyme 2, Coronavirus Infections
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