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Functional and structural characterization of the SARS-CoV-2 spike N481K mutation
Maria K Smatti1, Hebah Al-Khatib2, Muhammad Suleman2,3
1Biomedical Research Center, QU Health, Qatar University, PO Box 2713, Doha, Qatar. msmatti@qu.edu.qa.
Archives of Virology
|June 4, 2026
Summary
The N481K mutation in SARS-CoV-2 enhances binding to human ACE2 and shows partial evasion of antibody neutralization. This suggests increased viral fitness and potential for continued circulation.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- SARS-CoV-2 evolution is driven by selective pressures, particularly in the spike receptor-binding domain (RBD).
- The N481K RBD mutation, first detected in 2020, has re-emerged globally and is nearing fixation in Omicron lineages.
- The functional impact of the N481K mutation remained largely unexplored.
Purpose of the Study:
- To investigate the evolutionary trajectory and functional significance of the SARS-CoV-2 N481K RBD mutation.
- To assess the impact of N481K on ACE2 binding affinity and neutralization by antibodies from infected and vaccinated individuals.
Main Methods:
- Analysis of over 17 million SARS-CoV-2 genomes (2020-2025) to track N481K temporal and geographic circulation.
- Structural modeling, docking, and molecular dynamics simulations to evaluate ACE2 binding and RBD stability.
- In vitro neutralization assays using VSV pseudoviruses and sera from individuals infected with SARS-CoV-2 or vaccinated with mRNA, Sinopharm, or AstraZeneca vaccines.
Main Results:
- N481K prevalence reached near-fixation (>90%) in dominant Omicron lineages by 2024-2025, rising from 71.5% to 94.4%.
- Structural analyses revealed increased ACE2 binding affinity and enhanced stability for the N481K RBD compared to wild-type.
- Neutralization by antibodies was significantly reduced against N481K compared to wild-type, with the greatest reduction observed in sera from AstraZeneca, Sinopharm recipients, and infected individuals. mRNA vaccine recipients showed higher residual neutralization.
Conclusions:
- The N481K mutation confers increased viral fitness by enhancing ACE2 binding and partially evading antibody neutralization.
- These findings suggest that N481K contributes to the persistence of SARS-CoV-2 variants.
- Understanding the impact of such mutations is crucial for monitoring viral evolution and informing public health strategies.
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