Receptor-Specific Molecular Recognition of Maresin 1 and Docosahexaenoic Acid by the Nuclear Receptors PPARα, PPARγ, and RORα

Background/Objectives: Maresin 1 (MaR1), a pro-resolving mediator derived from docosahexaenoic acid (DHA), differs from DHA in its C7/C14 hydroxylation pattern and double-bond arrangement. We compared their recognition by peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), and retinoic acid receptor-related orphan receptor α (RORα) in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: We validated Glide docking by redocking reference ligands and performed four independent 250 ns molecular dynamics simulations per complex (24 trajectories; 6.0 μs). We evaluated structural stability, replica-resolved contacts, oxygen distance profiles, and conformational sampling; relative energetic estimates were obtained using molecular mechanics/generalized Born surface area (MM-GBSA) calculations. Results: Redocking RMSDs were ≤1.5 Å, and the replicated trajectories showed no ligand dissociation. In PPARα, MaR1 showed recurrent C7-OH–Lys358 proximity and reproducible carboxylate-associated contacts with Tyr314 and Ser280. In PPARγ, the MaR1 carboxylate sampled Tyr473 in helix 12 and HIE323 with replica-dependent geometry, whereas DHA retained an Arg288-centered anchor. In RORα, MaR1 preferentially sampled an Arg370-centered arrangement, whereas DHA predominantly engaged Arg367; both ligands displayed replica-dependent alternative polar contacts. MaR1 showed more negative hydrogen-bonding, lipophilic, and van der Waals contributions and lower numerical total MM-GBSA scores than DHA across all three receptor pairs. Conclusions: MaR1 showed receptor-specific redistribution of polar contacts associated with alternative carboxylate positioning. Although the calculations do not establish binding affinity or receptor activation, these patterns, rather than a conserved direct C7-OH/C14-OH recognition motif, define testable interaction sites for matched-analog studies and functional assays.