Structural and energetic profiling of SARS-CoV-2 receptor binding domain antibody recognition and the impact of circulating variants

PLoS Comput Biol. 2021 Sep 7;17(9):e1009380. doi: 10.1371/journal.pcbi.1009380. eCollection 2021 Sep.


The SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including Alpha (B.1.1.7) and Delta (B.1.617.2), some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. This detailed structure-based reference of antibody RBD recognition signatures can inform therapeutic and vaccine design strategies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Viral* / chemistry
  • Antibodies, Viral* / metabolism
  • Binding Sites
  • COVID-19 / virology*
  • Cluster Analysis
  • Computational Biology
  • Humans
  • Models, Molecular
  • Protein Binding
  • SARS-CoV-2 / genetics*
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Spike Glycoprotein, Coronavirus* / genetics
  • Spike Glycoprotein, Coronavirus* / metabolism


  • Antibodies, Viral
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2