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 ( ACE 2). The receptor binding domain ( RBD ) of S adopts two conformations: open and closed, respectively, accessible and inaccessible to ACE 2. Therefore, RBD motions are suspected to affect ACE 2 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 / ACE 2 interaction. Our results show that RBD dynamics affect ACE 2 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. ### Competing Interest Statement PSL valorization has submitted a patent related to the J-DNA forceps (PCT FR2018/053533) with DK, TS and CG among the inventors.