Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun 130023, People's Republic of China.
Phys Chem Chem Phys. 2020 Apr 29;22(16):8870-8877. doi: 10.1039/d0cp00763c.
Congenital adrenal hyperplasia (CAH) is one of the most frequent inborn errors of metabolism, inherited as an autosomal recessive trait. Above 95% of CAH cases are caused by mutations in cytochrome P450 21A2 (CYP21A2). It is a pity that how these mutations affect the structural characteristics and substrate binding of CYP21A2 is still unclear. To this end, molecular dynamics (MD) simulations and binding free energy calculations are performed to investigate the effects of single point mutations (L108R, G292C, G292S, G293D, and T296N) in CYP21A2. The results indicate that mutations could cause the local conformational changes of CYP21A2, affecting the substrate binding by changing the interaction between the protein and heme, changing the charge environment of residues, or introducing steric hindrance. In addition, our work gives a wonderful explanation of the phenomenon that though the substrate binding ability increases, the reaction activity decreases in T296N. The present study provides detailed atomistic insights into the structure-function relationships of CYP21A2, which could contribute to further understanding about 21-hydroxylase deficiency and also provide a theoretical basis for CAH prediction and treatment.
先天性肾上腺皮质增生症（CAH）是最常见的代谢性遗传缺陷之一，呈常染色体隐性遗传。超过 95%的 CAH 病例是由细胞色素 P450 21A2（CYP21A2）基因突变引起的。遗憾的是，这些突变如何影响 CYP21A2 的结构特征和底物结合仍不清楚。为此，我们进行了分子动力学（MD）模拟和结合自由能计算，以研究 CYP21A2 中单点突变（L108R、G292C、G292S、G293D 和 T296N）的影响。结果表明，突变可能导致 CYP21A2 的局部构象变化，通过改变蛋白质与血红素之间的相互作用、改变残基的电荷环境或引入空间位阻，影响底物结合。此外，我们的工作很好地解释了 T296N 中尽管底物结合能力增加，但反应活性降低的现象。本研究为 CYP21A2 的结构-功能关系提供了详细的原子水平见解，有助于进一步了解 21-羟化酶缺陷，并为 CAH 的预测和治疗提供理论基础。
