Impact of African-Specific ACE2 Polymorphisms on Omicron BA.4/5 RBD Binding and Allosteric Communication Within the...

Area of Science:

• Virology and Molecular Biology
• Genetics and Population Health
• Computational Biology

Background:

• Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection depends on the spike (S) protein's receptor binding domain (RBD) binding to human angiotensin-converting enzyme 2 (hACE2).
• Natural genetic variations (polymorphisms) in hACE2, especially at the binding interface, can modify these interactions and influence SARS-CoV-2 infectivity across diverse populations.

Purpose of the Study:

• To investigate the impact of six common hACE2 polymorphisms (S19P, K26R, M82I, K341R, N546D, D597Q) prevalent in African populations on their interaction with the SARS-CoV-2 Omicron BA.4/5 spike protein RBD.
• To elucidate the molecular mechanisms by which these hACE2 variants modulate viral binding and infectivity using computational analyses.

Main Methods:

• Employed post-molecular dynamics (MD) simulations to analyze the structural and dynamic consequences of hACE2 polymorphisms.
• Utilized inter-protein interaction analyses to quantify binding affinities and contact frequencies.
• Applied dynamic residue network (DRN) analyses to assess alterations in communication pathways within the hACE2 protein.

Main Results:

• The K26R hACE2 variant showed increased interactions, correlating with enhanced SARS-CoV-2 binding and susceptibility.
• S19P hACE2 exhibited reduced interactions and increased distances, suggesting hindered RBD binding, while M82I destabilized interactions.
• K341R demonstrated allosteric effects, increasing RBD-hACE2 contacts, and DRN analysis indicated altered network dynamics and impaired communication pathways for certain variants like M82I.

Conclusions:

• hACE2 polymorphisms significantly affect the stability of the SARS-CoV-2 BA.4/5 spike RBD interaction, modulating viral binding.
• These variations can influence SARS-CoV-2 infectivity in different populations, providing crucial insights for the development of targeted vaccines and therapeutics.
• Understanding the impact of genetic diversity on viral-host interactions is essential for effective pandemic preparedness and response.