Issue 16, 2020

How do mutations affect the structural characteristics and substrate binding of CYP21A2? An investigation by molecular dynamics simulations

Abstract

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.

Graphical abstract: How do mutations affect the structural characteristics and substrate binding of CYP21A2? An investigation by molecular dynamics simulations

Supplementary files

Article information

Article type
Paper
Submitted
11 feb 2020
Accepted
25 mar 2020
First published
27 mar 2020

Phys. Chem. Chem. Phys., 2020,22, 8870-8877

How do mutations affect the structural characteristics and substrate binding of CYP21A2? An investigation by molecular dynamics simulations

B. Lin, H. Zhang and Q. Zheng, Phys. Chem. Chem. Phys., 2020, 22, 8870 DOI: 10.1039/D0CP00763C

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements