SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics

Area of Science:

• Virology and Structural Biology
• Computational Biology and Bioinformatics
• Genetics and Genomics

Background:

• The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic highlighted the need for rapid understanding of viral composition and health outcomes.
• Coronaviruses' small RNA genomes facilitate cross-species spread and encode a complete set of viral proteins.
• A comprehensive understanding of viral proteomes and dynamicomes is crucial for pandemic response.

Purpose of the Study:

• To develop a comprehensive proteome- and dynamicome-level understanding of SARS-CoV-2 using integrated computational approaches.
• To establish the Viral Integrated Structural Evolution Dynamic Database (VIStEDD) for future research and education.
• To investigate the structural and dynamic properties of key SARS-CoV-2 proteins (nsp6, N, S) and their interactions with host factors.

Main Methods:

• Protein modeling and molecular dynamics simulations to analyze viral protein structures and dynamics.
• Evolutionary mapping to identify conserved regions and potential functional sites.
• Development of a quantitative dynamics cross-correlation matrix for analyzing protein-protein interactions.
• Creation of the VIStEDD database (RRID:SCR_018793) integrating structural and dynamic data.

Main Results:

• Identified highly conserved surface amino acids in nsp6 and nucleocapsid (N) proteins, suggesting roles in protein-protein interactions.
• Characterized the interaction between the SARS-CoV-2 spike (S) protein and the ACE2/SLC6A19 dimer using a novel dynamics matrix.
• Elucidated 47 potential functional missense variants in ACE2/SLC6A19/TMPRSS2, with some found in males hemizygous for ACE2.
• Identified two ACE2 noncoding variants (rs4646118, rs143185769) in individuals of African descent potentially linked to increased SARS-CoV-2 susceptibility.

Conclusions:

• The VIStEDD database provides a valuable resource for studying SARS-CoV-2 proteome and dynamicome.
• Conserved residues in nsp6 and N proteins are likely critical for viral function.
• Identified genetic variants in host factors (ACE2, SLC6A19, TMPRSS2) may influence SARS-CoV-2 infection dynamics and patient outcomes.
• Specific ACE2 variants may contribute to differential susceptibility among certain populations, warranting further genomic investigation.