Heteromerization As a Mechanism Modulating the Affinity of the ACE2 Receptor to the Receptor Binding Domain of SARS-CoV-2 Spike Protein

Background: Angiotensin-converting enzyme 2 (ACE2) is primarily involved in the ma-turation of angiotensin. It also represents the main receptor for the Severe Acute Respiratory Syn-drome coronavirus 2 (SARS-CoV-2) that caused a serious epidemic COVID-19. Available evi-dence indicates that at the cell membrane, ACE2 can form heteromeric complexes with other mem-brane proteins, including the amino acid transporter B0AT1 and G protein-coupled receptors (G-PCR). Objective: It is well known that during the formation of quaternary structures, the configuration of every single monomer is re-shaped by its interaction pattern in the macromolecular complex. There-fore, it can be hypothesized that the affinity of ACE2 to the viral receptor-binding domain (RBD), when in a heteromeric complex, may depend on the associated partner. Methods: By using established docking and molecular dynamics procedures, the reshaping of monomer was explored in silico to predict possible heterodimeric structures between ACE2 and GPCR, such as angiotensin and bradykinin receptors. The associated possible changes in the bind-ing affinity between the viral RBD and ACE2 when in the heteromeric complexes were also esti-mated. Results and Conclusion: The results provided support to the hypothesis that the heteromerization state of ACE2 may modulate its affinity to the viral RBD. If experimentally confirmed, ACE2 heteromerization may contribute to explain the observed differences in susceptibility to virus infec-tion among individuals and to devise new therapeutic opportunities.