Persistent cross-species SARS-CoV-2 variant infectivity predicted via comparative molecular dynamics simulation

Area of Science:

• Virology
• Molecular Biology
• Computational Biology

Background:

• Human transmission of SARS-CoV-2 has severe consequences.
• Reverse spillover from humans to wildlife, specifically bats, is a significant concern.
• Understanding viral binding to ACE2 receptors is crucial for assessing cross-species infectivity.

Purpose of the Study:

• To investigate the potential for human-to-bat SARS-CoV-2 cross-species infectivity.
• To compare the binding affinity of SARS-CoV-2 variants to bat and human ACE2 receptors.
• To analyze the molecular dynamics of receptor-binding domain (RBD)/ACE2 interactions.

Main Methods:

• Comparative statistical analyses of short-term molecular dynamic (MD) simulations.
• Statistical comparison of atom motion dampening upon RBD/ACE2 binding.
• Analysis of binding interfaces between SARS-CoV-2 RBD and bat (bACE2) vs. human (hACE2) receptors.

Main Results:

• The bat progenitor strain RaTG13 shows stronger affinity to bACE2 than hACE2, with some pre-adaptation to hACE2.
• Emergent human strains and variants of concern (VOCs) bind robustly to both bACE2 and hACE2.
• Delta and Omicron variants show evolutionary adaptation for binding to hACE2.

Conclusions:

• Despite adaptations, a significant risk of mammalian cross-species infectivity of human SARS-CoV-2 VOCs remains.
• This risk is particularly relevant as COVID-19 transitions to endemic status.
• Continued vigilance is necessary to monitor and mitigate potential reverse spillover events.