Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor

Area of Science:

• Virology
• Structural Biology
• Computational Biology

Background:

• Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) exhibits higher infectivity and pathogenicity compared to SARS-CoV.
• The spike protein's receptor binding domain (RBD) interaction with the human angiotensin converting enzyme 2 (ACE2) receptor is critical for viral entry.
• Existing X-ray structures do not fully explain the differential binding affinities between SARS-CoV-2 and SARS-CoV spike proteins to ACE2.

Purpose of the Study:

• To elucidate the molecular basis for the stronger binding affinity of SARS-CoV-2 spike protein to ACE2 compared to SARS-CoV.
• To investigate the role of thermal fluctuations and dynamics in the spike-ACE2 interaction.
• To provide insights for the design of novel antiviral therapeutics targeting the spike-ACE2 interaction.

Main Methods:

• All-atom molecular dynamics (MD) simulations were performed for microsecond timescales.
• Analysis of conformational binding modes, polar contacts, and their dynamics at the spike-ACE2 interface.
• Correlation analysis and thermodynamic calculations to understand residue interactions and coupling.

Main Results:

• SARS-CoV-2 spike-ACE2 interfaces exhibit similar conformational binding modes to SARS-CoV.
• SARS-CoV-2 spike interacts with ACE2 via a significantly larger number and different dynamics of polar contacts (45% more on average).
• Differences in polar contact density and dynamics are attributed to interfacial residue arrangements and allosteric coupling.

Conclusions:

• The enhanced binding of SARS-CoV-2 to ACE2 is mediated by a greater number and specific dynamics of polar contacts.
• Understanding the role of thermal fluctuations and allosteric effects is crucial for explaining binding affinity differences.
• Future drug design efforts targeting spike-ACE2 interactions should incorporate dynamic and allosteric information.