Article Dans Une Revue Nature Nanotechnology Année : 2025

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

Résumé

The first step of SARS-CoV-2 infection involves the interaction between the viral trimeric 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. Although these changes surely affect ACE2 binding, a quantitative description of the underlying mechanisms has remained elusive. Here we visualize RBD opening and closing using high-speed atomic force microscopy, gaining access to the corresponding transition rates. We also probe the S/ACE2 interaction at the ensemble level with biolayer interferometry and at the single-molecule level with atomic force microscopy and magnetic tweezers, evidencing that RBD dynamics hinder ACE2 binding but have no effect on unbinding. The resulting modulation is quantitatively predicted by a conformational selection model in which each S protomer behaves independently. Our work thus reveals a molecular mechanism by which RBD accessibility and binding strength can be tuned separately, providing hints to better understand the joint evolution of immune evasion and infectivity.

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hal-05109584 , version 1 (23-11-2025)

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Prithwidip Saha, Ignacio Fernandez, Fidan Sumbul, Claire Valotteau, Dorota Kostrz, et al.. Modulation of SARS-CoV-2 spike binding to ACE2 through conformational selection. Nature Nanotechnology, 2025, 20 (07), pp.926-934. ⟨10.1038/s41565-025-01908-1⟩. ⟨hal-05109584⟩
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