SARS-CoV-2 variants impact RBD conformational dynamics and ACE2 accessibility

Area of Science:

• Structural biology
• Virology
• Computational biophysics

Background:

• Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, poses a global health and economic threat.
• New variants of concern (VOCs) exhibit increased transmissibility and immune evasion due to mutations in the spike glycoprotein.
• The spike protein's receptor binding domain (RBD) mediates viral entry by binding to ACE2, but the impact of mutations on RBD dynamics is understudied.

Purpose of the Study:

• To investigate the effect of VOC mutations on the conformational dynamics of the SARS-CoV-2 RBD.
• To determine how these dynamic changes influence RBD-ACE2 binding affinity and potential antibody escape mechanisms.

Main Methods:

• Long atomistic molecular dynamics (AA-MD) simulations were employed.
• Simulations analyzed the structural dynamics of the wild-type (wt) RBD and four VOCs: Alpha, Beta, Delta, and Omicron.

Main Results:

• Wild-type RBD exists in two conformations: 'open' (ACE2-binding ready) and 'closed' (binding surface blocked).
• Alpha and Beta variants shifted the equilibrium towards the 'open' conformation, potentially increasing ACE2 binding.
• Delta and Omicron variants rarely adopted the 'closed' conformation. Delta exhibited an additional 'reversed' open conformation, potentially enhancing ACE2 binding and aiding antibody escape.

Conclusions:

• SARS-CoV-2 VOCs, particularly Delta and Omicron, significantly alter RBD conformational dynamics.
• These dynamic changes favor efficient ACE2 binding, contributing to viral fitness.
• The Delta variant's unique conformation may facilitate antibody escape, presenting a further challenge in COVID-19 control.