Self-Association of ACE-2 with Different RBD Amounts: A Dynamic Simulation Perspective on SARS-CoV-2 Infection

Area of Science:

• Molecular biology
• Virology
• Biophysics

Background:

• SARS-CoV-2 entry depends on Spike protein binding to ACE-2 receptors.
• ACE-2 self-association, influenced by Spike binding, is crucial for viral infection.
• Understanding Spike-ACE-2 complex formation is key to viral transmission.

Purpose of the Study:

• To investigate the self-association efficiency and conformational relevance of ACE-2 with varying amounts of bound Spike Receptor Binding Domains (RBDs).
• To elucidate the molecular mechanisms governing Spike-ACE-2 heteroprotein complex formation.
• To correlate ACE-2 self-association with SARS-CoV-2 viral activity.

Main Methods:

• Extensive coarse-grained dynamic simulations were employed.
• Characterization of self-association efficiency, conformational changes, and molecular interactions.
• Analysis of ACE-2 complexes with different RBD loading amounts (Mode-A: two/full RBDs, Mode-B: single RBD).

Main Results:

• ACE-2 bound to two/full RBDs (Mode-A) rapidly formed compact, linear heteroprotein dimers.
• ACE-2 bound to a single RBD (Mode-B) exhibited significant self-association and clustering.
• RBD-tethered ACE-2 ectodomains adopted a more upright conformation, with neck domain packing driving rapid self-association.

Conclusions:

• The amount of RBDs bound to ACE-2 dictates its self-association efficiency and complex conformation.
• Mode-B complexes, despite single RBD binding, maintain substantial self-association and clustering capabilities.
• These findings provide molecular insights into SARS-CoV-2 infection mechanisms and viral activity.