ALX/FPR2 Activation by Stereoisomers of D1 Resolvins Elucidating with Molecular Dynamics Simulation

Chronic inflammation contributes to several diseases,but its resolutionis driven by specialized pro-resolving mediators (SPM) such as resolvinD1 (RvD1) and its epimer aspirin-triggered resolvin D1 (AT-RvD1),both biosynthesized from & omega;-3 fatty docosahexaenoic acid (DHA).RvD1 and AT-RvD1 have anti-inflammatory and pro-resolution potentials,and their effects could be mediated by formyl peptide receptor type2 receptor ALX/FPR2, a G-protein-coupled receptor (GPCR). In thiswork, we performed 44 & mu;s of molecular dynamics simulations withtwo complexes: FPR2@AT-RvD1 and FPR2@RvD1. Our results show the following:(i) in the AT-RvD1 simulations, the ALX/FPR2 receptor remained inthe active state in 62% of the frames, while in the RVD1 simulations,the receptor remained in the active state in 74% of the frames; (ii)two residues, R201 and R205, of ALX/FPR2 appear, establishing interactionswith both resolvins in all simulations (22 in total); (iii) RvD1 hydrogenbonds with R201 and R205 presented higher frequency than AT-RvD1;and (iv) residues R201 and R205 are the two receptor hotspots, demonstratedby the binding free calculations. Such results show that the ALX/FPR2receptor remained in the active state for longer in the FPR2@RvD1simulations than in the FPR2@AT-RvD1 simulations.