title: PPARγ non-covalent antagonists exhibit mutable binding modes with a similar free energy of binding: a case study.
abstract: The structural and dynamical properties of PPARγ receptor in a complex with either partial or full agonists have been intensively studied but little is known about the receptor antagonistic conformation. A composition of microsecond accelerated molecular dynamics (aMD) simulation show that like partial agonists a non-covalent PPARγ full antagonist can bind in different modes of similar population size and free energies of binding. Four different and periodically exchanging ligand conformations are detected and described. The studied antagonist interacts with different receptor substructures and affects both the co-activator and the Cdk5 phosphorylation sites and, presumably, the natural complex with the DNA. However, no significant changes in the conformational states of the activation helix 12, and in particular an antagonist orientation, have been recorded. Finally, our results show also that the aMD approach can be successfully used in recovering the possible binding modes, considering fully the receptor flexibility, and is not dependent on the starting conformation.
authors.affiliation: a Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences , Acad. G. Bonchev Str., Block 105, 1113 Sofia , Bulgaria.
authors.forename: Filip
authors.initials: F
authors.lastname: Fratev
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D008024:Ligands; D047495:PPAR gamma
keywords: PPARγ; accelerated molecular dynamics (aMD); activation helix 12 (H12); antagonists; nuclear receptors