Stoichiometric insights into SARS-CoV-2 spike-ACE2 binding across variants.

Area of Science:

• Structural Biology
• Virology
• Computational Biophysics

Background:

• The SARS-CoV-2 spike protein facilitates viral entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.
• Mutations in SARS-CoV-2 variants alter spike protein binding affinity and conformational dynamics, influencing viral infectivity.

Purpose of the Study:

• To investigate the molecular dynamics and binding interactions of the Spike-ACE2 complex in wild-type (WT), Beta, and Delta SARS-CoV-2 variants.
• To elucidate variant-specific conformational changes and their impact on complex stability and ACE2 affinity.

Main Methods:

• Large-scale molecular dynamics simulations were employed to analyze the Spike-ACE2 complex.
• Binding free energy calculations were performed to quantify variant-specific ACE2 affinity.

Main Results:

• Significant conformational rearrangements were observed at the Spike-ACE2 interface in Beta and Delta variants compared to WT.
• Distinct interaction networks and altered complex stability were identified for the variants.
• Variant-specific differences in ACE2 affinity were revealed, with emerging alternative binding modes.

Conclusions:

• The study enhances understanding of spike-ACE2 stoichiometry across different SARS-CoV-2 variants.
• Findings provide implications for viral infectivity mechanisms and the development of targeted therapeutics.