AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Nucleocapsid Protein...

Area of Science:

• Virology
• Structural Biology
• Computational Biology

Background:

• The COVID-19 pandemic was characterized by the emergence of numerous Variants of Concern (VOCs).
• These VOCs exhibited enhanced transmissibility and infectivity due to specific mutant constellations.
• The evolutionary trajectory and origins of these VOCs remain incompletely understood.

Purpose of the Study:

• To investigate the evolutionary pathways of SARS-CoV-2 variants.
• To analyze the structural and functional impact of mutations on viral proteins, particularly the nucleocapsid (N) protein.
• To explore the potential of computational modeling for therapeutic interventions.

Main Methods:

• Utilized data mining and the GISAID database to establish a haplotype chronology up to July 2023.
• Employed ab initio methods to model the three-dimensional atomic structures of viral proteins.
• Investigated changes in the nucleocapsid (N) protein at sequence, structure, and biochemical levels, focusing on intrinsically disordered regions.

Main Results:

• Identified 22 haplotypes detailing viral evolution.
• Discovered that regions of intrinsic disorder in the nucleocapsid (N) protein were crucial for viral evolution.
• Observed significant mutations in the N-protein's linker region, impacting RNA binding, self-oligomerization, structure, and intrinsic disorder.
• Found that VOC constellations cooperatively modulated the effects of individual haplotypes.

Conclusions:

• The study highlights the critical role of intrinsically disordered regions in viral evolution.
• Demonstrates the utility of ab initio modeling and deep learning for understanding viral dynamics.
• Suggests a strategy for therapeutic intervention by mapping evolutionary landscapes to protein structures.