Abstract

The single nucleotide polymorphisms (SNPs) are the common genetic variations in human genomes and act as markers for molecular susceptibility of complex traits and diseases in humans. Amino acid variations in the non-synonymous SNPs (nsSNPs) in coding and non-coding regions affect the function/structure of the proteins. The Peroxisome proliferator-activated receptor gamma (PPARγ or PPARG) is a nuclear receptor that plays a significant role in lipid metabolism and insulin production and is associated with diabetes, obesity, and cancer. In this study, the PPARG sequence was retrieved from the NCBI database (dbSNP: NP_619726.2), and an analysis was done to predict the damaged/harmful mutated amino acids. We identified five mutated variants (C162S, R166W, Q286P, or Q314P and P467L), which were mostly expressed in cancer tissues and associated with insulin resistance and partial lipodystrophy. The identified mutations were induced, and the analysis of molecular dynamics simulation was established to determine the dynamic stability/flexibility of PPARG. The dynamic trajectories were analyzed by RMSD, RMSF, and Radius of Gyration (Rg) analysis; a vast difference was noticed in each of the protein structure when compared with the PPARG wild-type, and the mutations in PPARG impaired its functions, leading to more significant problems in humans.

Communicated by Ramaswamy H. Sarma

摘要

单核苷酸多态性（SNP）是人类基因组中常见的遗传变异，是人类复杂性状和疾病分子易感性的标志物。编码区和非编码区的非同义 SNP (nsSNP) 中的氨基酸变异会影响蛋白质的功能/结构。过氧化物酶体增殖物激活受体 γ（PPARγ 或 PPARG）是一种核受体，在脂质代谢和胰岛素产生中起重要作用，并且与糖尿病、肥胖和癌症有关。在本研究中，从 NCBI 数据库（dbSNP：NP_619726.2）中检索 PPARG 序列，并进行分析以预测受损/有害的突变氨基酸。我们鉴定了五种突变变体（C162S、R166W、Q286P 或 Q314P 和 P467L），它们主要在癌组织中表达，并与胰岛素抵抗和部分脂肪营养不良有关。诱导鉴定出的突变，并建立分子动力学模拟分析以确定PPARG的动态稳定性/灵活性。动态轨迹通过 RMSD、RMSF 和回转半径 (Rg) 分析进行分析；与 PPARG 野生型相比，每种蛋白质结构都存在巨大差异，并且 PPARG 的突变损害了其功能，导致人类出现更严重的问题。和回转半径 (Rg) 分析；与 PPARG 野生型相比，每种蛋白质结构都存在巨大差异，并且 PPARG 的突变损害了其功能，导致人类出现更严重的问题。和回转半径 (Rg) 分析；与 PPARG 野生型相比，每种蛋白质结构都存在巨大差异，并且 PPARG 的突变损害了其功能，导致人类出现更严重的问题。

由 Ramaswamy H. Sarma 传达