The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

Author summary Since early 2020, the trajectory of the COVID-19 pandemic has mostly been shaped by the appearance of novel variants of the SARS-CoV-2 virus. Accordingly, much of the scientific effort has been directed toward the question of explaining, understanding, and predicting the evolutionary fate of individual mutations in the viral genome. In this article, we focus on A222V, a particular mutation in the Spike protein that emerged in Spain in mid-2020 and reappeared independently in the AY.4.2 subvariant of Delta one year later. As reemerging mutations often indicate an evolutionary advantage, we explored potential mechanisms linking A222V to biologically relevant outcomes. Using serological, functional, structural, and computational approaches, we identified key molecular-level differences conferred by A222V that potentially explain its repeated emergence in different genetic backgrounds. Our results point to subtle changes in the dynamic behavior of the receptor-binding domain in the binding-competent "up" conformation, ones that affect receptor binding itself, but can also act synergistically with other mutations by changing the accessibility of key residues involved in molecular recognition.