Molecular Dynamics of PPAR Nuclear Receptors: From Ligand Binding to Transcriptional Regulation

Peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) are ligand-regulated nuclear receptors that coordinate lipid metabolism, glucose homeostasis, inflammation, adipogenesis, differentiation, and disease-associated transcriptional programs. Although early structural models emphasized ligand-dependent stabilization of helix 12 (H12) and the activation function-2 surface (AF-2), evidence from molecular dynamics (MD) simulations, NMR, HDX-MS, crystallography, mutagenesis, and biochemical assays supports a more complex conformational-ensemble mechanism. Apo and ligand-bound PPARs populate multiple functional substates whose distributions are shifted by ligands, RXR heterodimerization, DNA binding, co-regulators, post-translational modifications, and disease-associated mutations. This review summarizes MD and integrative structural studies of PPAR conformational dynamics, isoform-specific behavior, PPAR-RXR and co-regulator interactions, ligand entry, graded activation, inverse agonism, disease-associated mutations, and phosphorylation-dependent regulation. PPARγ is the most extensively characterized isoform, whereas PPARα and particularly PPARβ/δ remain comparatively underexplored by atomistic and enhanced-sampling approaches. MD is most informative when it extends beyond post-docking pose stability and is integrated with long-timescale sampling, free-energy methods, dynamic-network analysis, and experimental validation. Future simulations should increasingly model biologically realistic assemblies containing RXR, DNA, coactivators or corepressors, disease mutations, and post-translational modifications to connect ligand chemistry with receptor allostery, transcriptional output, and disease biology.