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

Background . Peroxisome proliferator-activated receptor- γ ( PPARγ ) gene is located at 3p25 position. PPAR γ 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). PPAR γ 1 and PPAR γ 2 are necessary for the development of adipose tissue and insulin sensitivity regulation. But PPAR γ 2 is the isoform that was controlled in response to nutrient intake and obesity. Methodology . In this study, we used computational techniques to show the impact of Pro12Ala polymorphism on PPAR γ 2. The 3-D structure of PPAR γ 2 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. Results and Conclusions . Stability prediction tools were showed that this mutation has a destabilizing effect on the PPAR γ 2 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 PPAR γ 2 protein and might disturb the conformational changes and interactions of PPAR γ 2 and results in type 2 diabetes mellitus (T2DM), CAD, and NAFLD. This study can help scientists to develop a drug therapy against these diseases.