Comparative analysis of ACE2 mutations and their impact on SARS-CoV-2 susceptibility within diverse ethnic groups

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has significantly impacted on global public health and economies. Emerging from China, the virus generated diverse variants with varying infectivity and drug resistance profiles. SARS-COV-2 requires an ACE-2 receptor for its adhesion, and and genetic analyses have identified multiple single-nucleotide variations in ACE2 across different human populations. We hypothesized that genetic polymorphisms influence susceptibility to infection by altering the binding affinity between ACE-2 and Spike protein. This study aimed to explore the susceptibility of five different ethnic regions (Africa, America, East Asia, Europe, and South Asia) to SARS-CoV-2 infection by employing in silico techniques. By introducing twenty-point mutations into a reference ACE2 structure, we conducted molecular dynamics (MD) simulations and utilized the MM/GBSA method to analyze the impact of these variations on ACE2's interaction with the viral spike protein. Our investigation revealed a spectrum of effects: 11 out of the 20 variations, predominantly found in the Asian population, were classified as deleterious, resulting in diminished susceptibility to the virus. Additionally, six variations, identified across Asian and African ethnicities, were categorized as potentially deleterious, with a potential to decrease binding affinity. Interestingly, two mutations sourced from European and American ethnic groups were considered neutral or enhancing, maintaining unaffected binding affinity. Conversely, one point mutation in the African population exhibited increased binding affinity, indicating increased vulnerability to viral attachment. These findings offer insights into the design of targeted therapeutics aimed at modulating the ACE2-spike protein interaction, thereby mitigating viral entry and infection.