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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月10日

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  • Prithwidip Saha,
  • Ignacio Fernandez,
  • Fidan Sumbul,
  • Claire Valotteau,
  • Dorota Kostrz,
  • Annalisa Meola,
  • Eduard Baquero,
  • Arvind Sharma,
  • James R. Portman,
  • François Stransky,
  • Thomas Boudier,
  • Pablo Guardado-Calvo,
  • Charlie Gosse,
  • Terence Strick,
  • Felix A. Rey,
  • Felix Rico

摘要

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.