Structural genetics of circulating variants affecting the SARS-CoV-2 spike/human ACE2 complex.

Area of Science:

• Virology
• Structural Biology
• Genomics

Background:

• SARS-CoV-2 enters human cells via the Spike protein binding to the ACE2 receptor.
• Mutations in Spike protein variants and human ACE2 alleles can alter this interaction.
• Antiviral strategies target the Spike-ACE2 interaction, necessitating understanding of variant effects.

Purpose of the Study:

• To identify key amino acids in Spike/ACE2 interaction using structural analysis.
• To correlate structural findings with SARS-CoV-2 mutational data.
• To identify ACE2 variants potentially affecting Spike interaction and infection susceptibility.

Main Methods:

• Applied Generalized Born Poisson-Boltzmann (GBPM) analysis to crystallographic structures.
• Analyzed structural data to pinpoint critical amino acids for Spike/ACE2 recognition.
• Intersected structural findings with mutational data from over 295,000 SARS-CoV-2 sequences.

Main Results:

• Identified key Spike mutations (S477N, N439K, N501Y, Y453F, E484K, K417N, S477I, G476S) interacting with ACE2 and present in at least 20 patients.
• Highlighted N501Y mutation as characteristic of the SARS-CoV-2 B.1.1.7 lineage.
• Discovered five rare ACE2 variants (S19P, E37K, M82I, E329G, G352V) potentially impacting Spike interaction and infection risk.

Conclusions:

• Structural and mutational analyses reveal specific Spike protein residues critical for ACE2 binding.
• Certain Spike mutations, like N501Y, are associated with prevalent SARS-CoV-2 lineages.
• Rare ACE2 variants may influence individual susceptibility to SARS-CoV-2 infection.