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 discover the viral composition and study health outcomes. The small ~30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread, but also enable a robust understanding of all the proteins the viral genome encodes. We have employed protein modeling, molecular dynamic 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 prokoplab.com/vistedd) 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.

Gene of the month:TMPRSS2(transmembrane serine protease 2)

“…24 The recent development of the Viral Integrated Structural Evolution Dynamic Database (VIStEDD) should help further elucidate the viral proteome dynamics and their interaction with host cell receptors. 25 Respiratory viruses with monobasic cleavage sites typically have an expression profile confined to the aerodigestive tract. Viral replication is limited to these organs as the cleavage site is cleaved by few cellular proteases, restricting viral growth to these limited areas.…”

“… 24 The recent development of the Viral Integrated Structural Evolution Dynamic Database (VIStEDD) should help further elucidate the viral proteome dynamics and their interaction with host cell receptors. 25 …”

Targeting SARS-CoV-2 nucleocapsid oligomerization: Insights from molecular docking and molecular dynamics simulations

“…Also, these residues are the most conserved residues of N protein according to multiple sequence alignment results obtained from ESPript 3.0 (Robert & Gouet, 2014) ( Figure S3, supplementary material). According to a recent study, the amino acids, 331-333 were the most conserved yet dynamic site of N and involved in the multimerization of N protein (Gupta et al, 2020). The multimeric structure of N revealed that the conserved amino acids Val270, Phe274, Arg277, Asn285, Gly287, Phe286, and Asp288 are clustered and surface exposed, and thus could contribute to protein-protein interactions.…”

SARS-CoV-2-Encoded Proteome and Human Genetics: From Interaction-Based to Ribosomal Biology Impact on Disease and Risk Processes

“…Structural level insights for coronavirus proteins are surprisingly deficient of human interaction partners. 10 A few of these proteins have been targeted for interaction assessments, such as the nucleocapsid protein 24 , 25 (shown below). It has been speculated that the understanding of virus–host interactions represents a major untapped potential of viral inhibitors.…”