Molecular Dynamics Simulation and Essential Dynamics of Deleterious Proline 12 Alanine Single-Nucleotide Polymorphism in PPAR2 Associated with Type 2 Diabetes, Cardiovascular Disease, and Nonalcoholic Fatty Liver Disease.

. Peroxisome proliferator-activated receptor- () gene is located at 3p25 position. PPAR functions as the master regulator of glucose homeostasis and lipoprotein metabolism, and recent studies have reported that it is involved in various metabolic diseases such as diabetes mellitus, hyperlipidemia, coronary artery disease (CAD), and nonalcoholic fatty liver disease (NAFLD). PPAR1 and PPAR2 are necessary for the development of adipose tissue and insulin sensitivity regulation. But PPAR2 is the isoform that was controlled in response to nutrient intake and obesity. . In this study, we used computational techniques to show the impact of Pro12Ala polymorphism on PPAR2. The 3-D structure of PPAR2 was modeled using I-TASSER server. The modeled structure was validated with the ZLab server, and the mutation was created with SPDB viewer. Stability prediction tools were used. Molecular dynamics simulation (MDS) was used to understand the structural and functional behavior of the wild type and mutant. Essential dynamics was also applied. . Stability prediction tools were showed that this mutation has a destabilizing effect on the PPAR2 structure. The RMSD, RMSF, Rg, SASA, and DSSP were in line with H-bond results that showed less flexibility in the mutant structure. Essential dynamics was used to verify MDS results. Pro12Ala polymorphism leads to rigidity of the PPAR2 protein and might disturb the conformational changes and interactions of PPAR2 and results in type 2 diabetes mellitus (T2DM), CAD, and NAFLD. This study can help scientists to develop a drug therapy against these diseases.