A rigorous framework for detecting SARS-CoV-2 spike protein mutational ensemble from genomic and structural features

Area of Science:

• Virology
• Structural Biology
• Genomics

Background:

• Genomic data reveals potential antigenic drift in SARS-CoV-2.
• Genomic instability in the spike protein requires investigation into viral-host interactions.

Purpose of the Study:

• To identify invariant and hypervariable regions in the SARS-CoV-2 spike protein.
• To analyze the structural impact of mutations in SARS-CoV-2 variants.
• To assess the implications for viral pathogenesis and vaccine efficacy.

Main Methods:

• Temporal tracking of 527,988 SARS-CoV-2 genomes.
• Evaluation of mutation combinations across SARS-CoV-2 lineages.
• Analysis of 3D-structural models of Variants of Concern (VOCs).
• Molecular dynamics simulations of D614G mutant spike protein with hACE2.

Main Results:

• Invariant and hypervariable regions identified in the spike protein.
• N-terminal domain (NTD) harbors the most lineage-defining mutations.
• Mutations significantly alter structural properties like accessibility and intra-protein interactions.
• Delta mutant shows denser intra-protein contacts compared to wild-type.
• 47.7% of mutations map to flexible regions of the spike protein.

Conclusions:

• Significant structural changes in the SARS-CoV-2 spike protein may affect pathogenesis.
• Repositioning of vaccine candidates is crucial to combat the spread of COVID-19.
• Further exploration of viral-host interactions is warranted.