Genetic variations affecting ACE2 protein stability in minority populations

Area of Science:

• Computational biology
• Virology
• Genetics

Background:

• The SARS-CoV-2 spike glycoprotein targets Angiotensin-converting enzyme-2 (ACE2) for human cell entry.
• Understanding genetic variations in ACE2 and their impact on protein stability is crucial for developing effective COVID-19 treatments.

Purpose of the Study:

• To investigate the effects of all possible mutations in ACE2 proteins on the stability of ACE2-SARS-CoV-1-S and ACE2-SARS-CoV-2-S complexes.
• To identify specific ACE2 genetic variations that influence the stability of the ACE2-SARS-CoV-2-S interaction, particularly in minority populations.

Main Methods:

• Computational saturation mutagenesis was employed to analyze the folding energy of all potential ACE2 mutations.
• Analysis focused on ACE2-SARS-CoV-1-S and ACE2-SARS-CoV-2-S complexes.
• Specific ACE2 genetic variations (SNPs) were identified and their impact on protein stability assessed.

Main Results:

• Mutations at residue D350 in ACE2 demonstrated the most significant stabilizing effect on the protein.
• Several ACE2 genetic variations were identified in African Americans and Latino Americans that affect ACE2-SARS-CoV-2-S complex stability.
• Specific rs numbers (e.g., rs73635825, rs924799658) were linked to stability changes.

Conclusions:

• ACE2 protein stability is influenced by specific mutations, notably at D350.
• Identified genetic variations in ACE2 within minority populations may alter SARS-CoV-2 binding and stability.
• These findings can inform the development of targeted therapies, such as stable neutralizing peptides, for diverse patient groups.