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Updated: Sep 6, 2025

Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution
Tyler N Starr1, Allison J Greaney1,2,3, William W Hannon1,4
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved variants with substitutions in the spike receptor-binding domain (RBD) that affect its affinity for angiotensin-converting enzyme 2 (ACE2) receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites-a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single-amino acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently Asn501→Tyr (N501Y), cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change-for example, enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.
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