Nuclear Hormone Receptors (NRs) are major targets for pharmaceuticaldevelopment. Many experiments demonstrate that their C-terminal Helix(H12) is more flexible in the Ligand Binding Domains (LBDs) withoutligand, this increased mobility being correlated with transcriptionrepression and human diseases. Crystal structures have been obtained inwhich the H12 is extended, suggesting the possibility of large amplitudeH12 motions in solution. However, these structures were interpreted aspossible crystallographic artifacts, and thus the microscopic nature ofH12 movements is not well known. In order to bridge the gap betweenexperiments and molecular models and provide a definitive picture of H12motions in solution, extensive Molecular Dynamics Simulations of thePeroxisome Proliferator-Activated Receptor-$\gamma$ LBD, in which theH12 was bound to a fluorescent probe, were performed. A directcomparison of the modeled anisotropy decays to time-resolvedfluorescence anisotropy experiments was obtained. It is shown that thedecay rates are dependent on the interactions of the probe with thesurface of the protein, and display little correlation with theflexibility of the H12. Nevertheless, for the probe to interact with thesurface of the LBD, the H12 must must be folded over the body of theLBD. Therefore, the molecular mobility of the H12 should preserve theglobularity of the LBD, so that ligand binding and dissociation shouldoccur by diffusion through the surface of a compact receptor. Theseresults advance the comprehension both ligand-bound and ligand-freereceptor structures in solution, and also guide the interpretation oftime-resolved anisotropy decays from a molecular perspective,particularly by the use of simulations. (AU)