Taghvaei Somayye, Saremi Leila
Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
PPAR Res. 2022 May 2;2022:3833668. doi: 10.1155/2022/3833668. eCollection 2022.
. 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.
过氧化物酶体增殖物激活受体-（）基因位于3p25位置。PPAR作为葡萄糖稳态和脂蛋白代谢的主要调节因子，最近的研究报道它参与了多种代谢性疾病，如糖尿病、高脂血症、冠状动脉疾病（CAD）和非酒精性脂肪性肝病（NAFLD）。PPAR1和PPAR2对于脂肪组织的发育和胰岛素敏感性调节是必需的。但PPAR2是受营养摄入和肥胖影响而被调控的异构体。在本研究中，我们使用计算技术来展示Pro12Ala多态性对PPAR2的影响。使用I-TASSER服务器对PPAR2的三维结构进行建模。使用ZLab服务器对建模结构进行验证，并使用SPDB查看器创建突变。使用稳定性预测工具。分子动力学模拟（MDS）用于了解野生型和突变体的结构和功能行为。还应用了主成分动力学。稳定性预测工具表明，这种突变对PPAR2结构具有去稳定作用。均方根偏差（RMSD）、均方根波动（RMSF）、回旋半径（Rg）、溶剂可及表面积（SASA）和二级结构预测（DSSP）与氢键结果一致，表明突变体结构的灵活性较低。主成分动力学用于验证MDS结果。Pro12Ala多态性导致PPAR2蛋白刚性增加，可能会干扰PPAR2的构象变化和相互作用，从而导致2型糖尿病（T2DM）、CAD和NAFLD。本研究有助于科学家开发针对这些疾病的药物治疗方法。
