Modulation of SARS-CoV-2 spike binding to ACE2 through conformational selection
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The first step of SARS-CoV-2 infection involves the interaction between the trimeric viral spike protein (π) and the host angiotensin-converting enzyme 2 (π΄πΆπΈ2). The receptor binding domain (π π΅π·) of π adopts two conformations: open and closed, respectively, accessible and inaccessible to π΄πΆπΈ2. Therefore, π π΅π· motions are suspected to affect π΄πΆπΈ2 binding; yet a quantitative description of the underlying mechanism has been elusive. Here, using single-molecule approaches, we visualize π π΅π· opening and closing and probe the π/π΄πΆπΈ2 interaction. Our results show that RBD dynamics affect π΄πΆπΈ2 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.