Solayman Md, Saleh Md Abu, Paul Sudip, Khalil Md Ibrahim, Gan Siew Hua
Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh.
Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh; Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne 3004, Victoria, Australia.
Comput Biol Chem. 2017 Jun;68:175-185. doi: 10.1016/j.compbiolchem.2017.03.005. Epub 2017 Mar 14.
Polymorphisms of the ADIPOR2 gene are frequently linked to a higher risk of developing diseases including obesity, type 2 diabetes and cardiovascular diseases. Though mutations of the ADIPOR2 gene are detrimental, there is a lack of comprehensive in silico analyses of the functional and structural impacts at the protein level. Considering the involvement of ADIPOR2 in glucose uptake and fatty acid oxidation, an in silico functional analysis was conducted to explore the possible association between genetic mutations and phenotypic variations. A genomic analysis of 82 nonsynonymous SNPs in ADIPOR2 was initiated using SIFT followed by the SNAP2, nsSNPAnalyzer, PolyPhen-2, SNPs&GO, FATHMM and PROVEAN servers. A total of 10 mutations (R126W, L160Q, L195P, F201S, L235R, L235P, L256R, Y328H, E334K and Q349H) were predicted to have deleterious effects on the ADIPOR2 protein and were therefore selected for further analysis. Theoretical models of the variants were generated by comparative modeling via MODELLER 9.16. A protein structural analysis of these amino acid variants was performed using SNPeffect, I-Mutant, ConSurf, Swiss-PDB Viewer and NetSurfP to explore their solvent accessibility, molecular dynamics and energy minimization calculations. In addition, FTSite was used to predict the ligand binding sites, while NetGlycate, NetPhos2.0, UbPerd and SUMOplot were used to predict post-translational modification sites. All of the variants showed increased free energy, though F201S exhibited the highest energy increase. The root mean square deviation values of the modeled mutants strongly indicated likely pathogenicity. Remarkably, three binding sites were detected on ADIPOR2, and two mutations at positions 328 and 201 were found in the first and second binding pockets, respectively. Interestingly, no mutations were found at the post-translational modification sites. These genetic variants can provide a better understanding of the wide range of disease susceptibility associated with ADIPOR2 and aid the development of new molecular diagnostic markers for these diseases. The findings may also facilitate the development of novel therapeutic elements for associated diseases.
ADIPOR2基因的多态性常常与包括肥胖症、2型糖尿病和心血管疾病在内的多种疾病的高发风险相关联。尽管ADIPOR2基因的突变具有有害性，但目前缺乏对其在蛋白质水平上功能和结构影响的全面计算机模拟分析。鉴于ADIPOR2参与葡萄糖摄取和脂肪酸氧化过程，我们进行了一项计算机模拟功能分析，以探究基因突变与表型变异之间的可能关联。我们首先使用SIFT对ADIPOR2基因中的82个非同义单核苷酸多态性（SNP）进行基因组分析，随后利用SNAP2、nsSNPAnalyzer、PolyPhen - 2、SNPs&GO、FATHMM和PROVEAN服务器进行分析。总共10个突变（R126W、L160Q、L195P、F201S、L235R、L235P、L256R、Y328H、E334K和Q349H）被预测对ADIPOR2蛋白具有有害影响，因此被选作进一步分析。通过MODELLER 9.16进行比较建模生成了这些变体的理论模型。利用SNPeffect、I - Mutant、ConSurf、Swiss - PDB Viewer和NetSurfP对这些氨基酸变体进行蛋白质结构分析，以探究它们的溶剂可及性、分子动力学和能量最小化计算。此外，使用FTSite预测配体结合位点，同时使用NetGlycate、NetPhos2.0、UbPerd和SUMOplot预测翻译后修饰位点。所有变体均显示自由能增加，尽管F201S的能量增加幅度最大。建模突变体的均方根偏差值强烈表明其可能具有致病性。值得注意的是，在ADIPOR2上检测到三个结合位点，并且在第一和第二结合口袋中分别发现了位于328和201位的两个突变。有趣的是，在翻译后修饰位点未发现突变。这些基因变体有助于更好地理解与ADIPOR2相关的广泛疾病易感性，并有助于开发针对这些疾病的新型分子诊断标志物。这些发现也可能促进针对相关疾病的新型治疗元件的开发。
