SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets

Area of Science:

• Structural biology
• Virology
• Biophysics

Background:

• The SARS-CoV-2 spike (S) protein mediates viral entry into host cells by binding to angiotensin-converting enzyme 2 (ACE2) receptors.
• The precise mechanism by which ACE2 binding initiates S protein proteolysis, a crucial step for viral entry, remains largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying ACE2 binding-induced allosteric changes in the SARS-CoV-2 spike protein.
• To map the S protein-ACE2 interaction interface and understand its impact on distal functional sites.

Main Methods:

• Amide hydrogen-deuterium exchange mass spectrometry (HDX-MS) was employed to map the S:ACE2 interaction interface.
• Molecular dynamics (MD) simulations were utilized to investigate the dynamic consequences of ACE2 binding on the S protein.

Main Results:

• ACE2 binding was found to allosterically enhance dynamics at the S1/S2 cleavage site and flanking protease docking sites (~27 Å away).
• Conversely, ACE2 binding dampened dynamics in the stalk hinge regions (central helix and heptad repeat [HR]) (~130 Å away).
• These findings reveal the stalk and proteolysis sites as dynamic hotspots in the prefusion state of the S protein.

Conclusions:

• The study provides a detailed dynamics map of the S:ACE2 interface in solution, offering mechanistic insights into allosteric coupling.
• ACE2 binding is shown to be allosterically linked to distal proteolytic processing sites, facilitating viral-host membrane fusion.
• Protease docking sites near the S1/S2 cleavage site emerge as potential allosteric targets for therapeutic intervention against SARS-CoV-2.