Abstract
Nine structures of the ALX/FPR2 receptor are currently deposited in the PDB. In seven structures, the receptor is complexed with formylated peptides. In all seven structures, residue D106 is indicated as acting in the ALX/FPR2 receptor activation in addition to residues R201 and R205. Here, we performed docking simulations and long-term molecular dynamics simulations to investigate the ALX/FPR2 receptor activation using two pro-resolution agonists (lipoxin A4 (LXA(4)) and resolvin D3 (RvD3)) and a formylated peptide pro-inflammatory agonist (fMLFII). We have analyzed the receptor's activation state, electrostatic interactions, and the binding affinities of the complexes receptor-agonist using the MM/PBSA approach. The results showed that LXA(4) and fMLFII kept the receptor in an active state by a higher simulation time when compared to RvD3. Only R201 and R205 were considered key residues in the ALX/FPR2 receptor activation by all agonists. The electrostatic interaction analysis confirmed the importance of these residues in ALX/FPR2 receptor activation. Furthermore, only fMLLII showed interactions with residue D106. The binding free energy calculations indicated that the electrostatic component significantly binds the agonists to the receptor. Overall, the results from this study provide new insights into the ALX/FPR2 receptor activation mechanisms, reinforcing the role of critical residues and interactions in the binding of pro-resolution and inflammatory agonists.