Examination of the interactions of angiotensin 1-7 peptide with angiotensin receptor type2 and proto-oncogene mas receptor by in-silico methods

Objective: It is aimed to elucidate the molecular mechanisms in a protective arm of the Renin-Angiotensin System (RAS) by determining the ligand-receptor interactions of Ang 1-7 peptide with AT2R and proto-oncogene MAS receptor, changes in receptor dynamics with ligand binding, and GPCR activation mechanisms in the RAS. Method: Molecular docking of Ang 1-7 and Ang II peptides with AT2R and MAS receptors was performed. By using the first binding poses, complex structures were obtained for the inactive and active-like structures of the receptors, with and without ligands. After these structures were placed on the membrane, input files were prepared and MD simulations with 1-microsecond duration were carried out. The trajectory files obtained from the simulations were analyzed using many in-silico programs. Results: Ang 1-7 and Ang II ligands showed stable binding to the inactive and active-like structures of AT2R and Ang 1-7 ligand to the inactive and active-like structures of MAS receptor throughout 1-microsecond MD simulation. Although Ang 1-7 and Ang II ligand binding had an effect on the structural dynamics of AT2R, but they did not affect receptor activation. It was found that Ang 1-7 ligand binding may affect both the structural dynamics of the MAS receptor and play an effective role in receptor activation. Conclusion: It was thought that the interaction of Ang 1-7 with MAS may be more effective in the RAS compared to AT2R. Besides, It has led to the suggestion that Ang II binding may help to prolong the stable time of AT2R in the active state and increase the probability of intracellular G-protein binding. It is thought that oligomerization and G-protein binding should also be examined to understand the molecular mechanisms of receptors. Keywords: RAS, Ang 1-7, AT2R, MAS, MD Simulation