Issue 3, 2011

Predicting the coordination geometry for Mg2+ in the p53 DNA-binding domain: insights from computational studies

Abstract

Zn2+ in the tumor-suppressor protein p53 DNA-binding domain (DBD) is essential for its structural stability and DNA-binding specificity. Mg2+ has also been recently reported to bind to the p53DBD and influence its DNA-binding activity. In this contribution, the binding geometry of Mg2+ in the p53DBD and the mechanism of how Mg2+ affects its DNA-binding activity were investigated using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Various possible coordination geometries of Mg2+ binding to histidines (His), cysteines (Cys), and water molecules were studied at the B3LYP/6-311+g** level of theory. The protonation state of Cys and the environment were taken into account to explore the factors governing the coordination geometry. The free energy of the reaction to form the Mg2+ complexes was estimated, suggesting that the favorable binding mode changes from a four- to six-coordinated geometry as the number of the protonated Cys increases. Furthermore, MD simulations were employed to explore the binding modes of Mg2+ in the active site of the p53DBD. The simulation results of the Mg2+ system and the native Zn2+ system show that the binding affinity of Mg2+to the p53DBD is weaker than that of Zn2+, in agreement with the DFT calculation results and experiments. In addition, the two metal ions are found to make a significant contribution to maintain a favorable orientation for Arg248 to interact with putative DNA, which is critically important to the sequence-specific DNA-binding activity of the p53DBD. However, the effect of Mg2+ is less marked. Additionally, analysis of the natural bond orbital (NBO) charge transfer reveals that Mg2+ has a higher net positive charge than Zn2+, leading to a stronger electrostatic attractive interaction between Mg2+ and putative DNA. This may partly explain the higher sequence-independent DNA-binding affinity of p53DBD–Mg2+ compared to p53DBD–Zn2+ observed in experiment.

Graphical abstract: Predicting the coordination geometry for Mg2+ in the p53 DNA-binding domain: insights from computational studies

Supplementary files

Article information

Article type
Paper
Submitted
25 May 2010
Accepted
27 Sep 2010
First published
15 Nov 2010

Phys. Chem. Chem. Phys., 2011,13, 1140-1151

Predicting the coordination geometry for Mg2+ in the p53 DNA-binding domain: insights from computational studies

T. Wang, X. Shao, W. Cai, Y. Xue, S. Wang and X. Feng, Phys. Chem. Chem. Phys., 2011, 13, 1140 DOI: 10.1039/C0CP00678E

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