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

Area of Science:

• Virology
• Structural Biology
• Biophysics

Background:

• SARS-CoV-2 infection initiates via interaction between the viral spike protein (S) and host ACE2.
• The S protein's receptor-binding domain (RBD) exists in open and closed states, affecting ACE2 accessibility.

Purpose of the Study:

• To quantitatively describe the mechanisms underlying RBD conformational changes and their impact on ACE2 binding.
• To investigate the dynamics of RBD opening and closing and their effect on SARS-CoV-2 infectivity.

Main Methods:

• High-speed atomic force microscopy (HS-AFM) to visualize RBD opening/closing dynamics and transition rates.
• Biolayer interferometry (BLI) for ensemble-level S/ACE2 interaction analysis.
• Single-molecule force spectroscopy (AFM and magnetic tweezers) to probe S/ACE2 binding kinetics.

Main Results:

• HS-AFM provided visualization of RBD conformational transitions and their rates.
• RBD dynamics were found to impede ACE2 binding but not affect unbinding.
• A conformational selection model quantitatively predicted the observed modulation of binding.

Conclusions:

• RBD accessibility and binding strength can be independently regulated by conformational dynamics.
• This provides insights into the molecular mechanisms governing SARS-CoV-2 infectivity and immune evasion.
• Findings offer potential targets for therapeutic strategies against SARS-CoV-2.