Modulation of SARS-CoV-2 spike binding to ACE2 throughconformational selection

Saha, P.; Fernanadez, I.; Sumbul, F.; Valotteau, C.; Kostrz, D.; Meola, A.; Baquero, E.; Sharma, A.; Portman, J. R.; Stransky, F.; Boudier, T.; Guardado Calvo, P.; Gosse, C.; Strick, T.; Rey, F. A.; Rico, F.

doi:10.1101/2024.03.15.585207

bioRxiv · 10.1101/2024.03.15.585207

Modulation of SARS-CoV-2 spike binding to ACE2 throughconformational selection

Saha, P.·Fernanadez, I.·Sumbul, F.·Valotteau, C.·Kostrz, D.·Meola, A.·Baquero, E.·Sharma, A.·Portman, J. R.·Stransky, F.·Boudier, T.·Guardado Calvo, P.·Gosse, C.·Strick, T.·Rey, F. A.·Rico, F.

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Abstract

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.

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Saha, P., Fernanadez, I., Sumbul, F., Valotteau, C., Kostrz, D., Meola, A., Baquero, E., Sharma, A., Portman, J. R., Stransky, F., Boudier, T., Guardado Calvo, P., Gosse, C., Strick, T., Rey, F. A., Rico, F.. 2024-03-18. Modulation of SARS-CoV-2 spike binding to ACE2 throughconformational selection. https://doi.org/10.1101/2024.03.15.585207

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