In silico screening, molecular docking, and molecular dynamics studies of SNP-derived human P5CR mutants
In silico screening, molecular docking, and molecular dynamics studies of SNP-derived human P5CR mutants
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SNP 衍生的人类 P5CR 突变体的计算机筛选、分子对接和分子动力学研究
DOI：
10.1080/07391102.2016.1222967
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Meng, Zhao-Hui
中科院分区：
文献类型：
--
作者：
Sang, Peng;Hu, Wei;Meng, Zhao-Hui
PYCR1基因编码的吡咯烷-5-羧酸还原酶(P5CR)是一种以NAD(P)H为辅因子催化P5C还原为Pro的看家酶。在这项研究中，我们使用电子计算机方法检测了PYCR1基因的非同义单核苷酸多态在皮肤松弛发病机制中的作用及其可能的功能。在已鉴定的348个SNP中，有15个被SIFT和PolyPhen工具预测具有潜在的破坏性；其中两个SNP衍生的突变R119G和G206W先前已被报道与皮肤松弛相关。因此，这两个突变被选为野生型(WT)P5CR结构的图谱，用于进一步的结构和功能分析。使用I-Mutant和Autodock的比较计算分析结果表明，这两个突变体的稳定性和辅因子结合亲和力都降低了。用比较分子动力学(MD)模拟来评估突变后P5CR的动力学性质的变化。结果表明，这两个突变增强了P5CR结构的刚性，特别是辅因子结合部位的刚性，从而导致辅因子进出动力学的降低。在MD模拟中对WT和突变体的结构性质进行了比较，结果表明突变体刚性的增强很可能是由于原子间相互作用数量的增加和动态氢键数量的减少。我们的研究为R119G和G206W突变对P5CR的有害影响提供了新的见解，并揭示了这些突变介导皮肤松弛的机制。
Pyrroline-5-carboxylate reductase (P5CR) encoded by PYCR1 gene is a housekeeping enzyme that catalyzes the reduction of P5C to proline using NAD(P)H as the cofactor. In this study, we used in silico approaches to examine the role of nonsynonymous single-nucleotide polymorphisms in the PYCR1 gene and their putative functions in the pathogenesis of Cutis Laxa. Among the 348 identified SNPs, 15 were predicted to be potentially damaging by both SIFT and PolyPhen tools; of them two SNP‐derived mutations, R119G and G206W, have been previously reported to correlate with Cutis Laxa. These two mutations were therefore selected to be mapped to the wild‐type (WT) P5CR structure for further structural and functional analyses. The results of comparative computational analyses using I-Mutant and Autodock reveal reductions in both stability and cofactor binding affinity of these two mutants. Comparative molecular dynamics (MD) simulations were performed to evaluate the changes in dynamic properties of P5CR upon mutations. The results reveal that the two mutations enhance the rigidity of P5CR structure, especially that of cofactor binding site, which could result in decreased kinetics of cofactor entrance and egress. Comparison between the structural properties of the WT and mutants during MD simulations shows that the enhanced rigidity of mutants results most likely from the increased number of inter‐atomic interactions and the decreased number of dynamic hydrogen bonds. Our study provides novel insight into the deleterious effects of the R119G and G206W mutations on P5CR, and sheds light on the mechanisms by which these mutations mediate Cutis Laxa.