Background: Angiotensin-converting enzyme 2 (ACE2) is primarily involved in the maturation
of angiotensin. It also represents the main receptor for the Severe Acute Respiratory Syndrome
coronavirus 2 (SARS-CoV-2) that caused a serious epidemic COVID-19. Available evidence
indicates that at the cell membrane, ACE2 can form heteromeric complexes with other membrane
proteins, including the amino acid transporter B0 AT1 and G protein-coupled receptors (GPCR).
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. Therefore,
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 binding
affinity between the viral RBD and ACE2 when in the heteromeric complexes were also estimated.
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 infection
among individuals and to devise new therapeutic opportunities.