Modulation of SARS-CoV-2 spike binding to ACE2 through conformational selection

The first step of SARS-CoV-2 infection involves the interaction between the trimeric viral spike protein (𝑆) and the host angiotensin-converting enzyme 2 (𝐴𝐶𝐸2). The receptor binding domain (𝑅𝐵𝐷) of 𝑆 adopts two conformations: open and closed, respectively, accessible and inaccessible to 𝐴𝐶𝐸2. Therefore, 𝑅𝐵𝐷 motions are suspected to affect 𝐴𝐶𝐸2 binding; yet a quantitative description of the underlying mechanism has been elusive. Here, using single-molecule approaches, we visualize 𝑅𝐵𝐷 opening and closing and probe the 𝑆/𝐴𝐶𝐸2 interaction. Our results show that RBD dynamics affect 𝐴𝐶𝐸2 binding but not unbinding. The resulting modulation is quantitatively predicted by a conformational selection model in which each protomer behaves independently. Our work reveals a general molecular mechanism affecting binding affinity without altering binding strength, helping to understand coronavirus infection and immune evasion.