The peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important transcription factor that plays a major role in the regulation of glucose and lipid metabolisms and has, therefore, many implications in modern-life metabolic disorders such as diabetes, obesity, and cardiovascular diseases. Phosphorylation of PPAR gamma by the cyclin-dependent kinase 5 (Cdk5) has been recently proved to promote obesity and loss of insulin sensitivity. The inhibition of this reaction is currently being pursued to develop PPAR gamma ligands for type 2 diabetes treatments. The knowledge of the protein protein interactions between CdkS/p25 and PPAR gamma can be an important asset for better understanding of the molecular basis of the Cdk5-meditated phosphorylation Of PPAR gamma and its inhibition: By means of a computational approach that combines protein protein docking and adaptive biasing force molecular dynamics simulations, we obtained PPAR gamma-Cdk5/p25 structural models that are consistent with the mechanism of the enzymatic reaction and with overall structural features of the full length PPAR gamma-RXR alpha heterodimer bound to DNA. In addition to the active site, our model shows that the interacting regions between the two proteins should involve two distal docking sites, comprising the PPAR gamma Omega-loop and Cdk5 N-terminal lobe and the PPAR gamma beta-sheet and Cdk5 C-terminal lobe. These sites are related to PPAR gamma transactivation and directly interact with PPAR gamma-ligands. Our results suggest that beta-sheets and Omega-loop stabilization promoted by PPAR gamma agonists could be important to inhibit Cdk5-mediated phosphorylation.