Journal of Molecular Modeling

, 20:2500 | Cite as

Understanding the recognition mechanisms of Zα domain of human editing enzyme ADAR1 (hZαADAR1) and various Z-DNAs from molecular dynamics simulation

  • Qianqian Wang
  • Lanlan Li
  • Xiaoting Wang
  • Huanxiang Liu
  • Xiaojun Yao
Original Paper
First Online:
Received:
Accepted:

Abstract

The Z-DNA-binding domain of human double-stranded RNA adenosine deaminase I (hZαADAR1) can specifically recognize the left-handed Z-DNA which preferentially occurs at alternating purine-pyrimidine repeats, especially the CG-repeats. The interactions of hZαADAR1 and Z-DNAs in different sequence contexts can affect many important biological functions including gene regulation and chromatin remodeling. Therefore it is of great necessity to fully understand their recognition mechanisms. However, most existing studies are aimed at the standard CG-repeat Z-DNA rather than the non-CG-repeats, and whether the molecular basis of hZαADAR1 binding to various Z-DNAs are identical or not is still unclear on the atomic level. Here, based on the recently determined crystal structures of three representative non-CG-repeat Z-DNAs (d(CACGTG)2, d(CGTACG)2 and d(CGGCCG)2) in complex with hZαADAR1, 40 ns molecular dynamics simulation together with binding free energy calculation were performed for each system. For comparison, the standard CG-repeat Z-DNA (d(CGCGCG)2) complexed with hZαADAR1 was also simulated. The consistent results demonstrate that nonpolar interaction is the driving force during the protein-DNA binding process, and that polar interaction mainly from helix α3 also provides important contributions. Five common hot-spot residues were identified, namely Lys169, Lys170, Asn173, Arg174 and Tyr177. Hydrogen bond analysis coupled with surface charge distribution further reveal the interfacial information between hZαADAR1 and Z-DNA in detail. All of the analysis illustrate that four complexes share the common key features and the similar binding modes irrespective of Z-DNA sequences, suggesting that Z-DNA recognition by hZαADAR1 is conformation-specific rather than sequence-specific. Additionally, by analyzing the conformational changes of hZαADAR1, we found that the binding of Z-DNA could effectively stabilize hZαADAR1 protein. Our study can provide some valuable information for better understanding the binding mechanism between hZαADAR1 or even other Z-DNA-binding protein and Z-DNA.

Keywords

Binding free energy Molecular dynamics simulation Protein-DNA interaction Recognition mechanism 
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Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No 21175063) and the Natural Science Foundation of Gansu Province, China (Grant No: 1208RJYA034).

Supplementary material

894_2014_2500_MOESM1_ESM.doc (83 kb)
ESM 1 (DOC 83 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Qianqian Wang
    • 1
  • Lanlan Li
    • 1
  • Xiaoting Wang
    • 2
  • Huanxiang Liu
    • 1
  • Xiaojun Yao
    • 2
  1. 1.School of PharmacyLanzhou UniversityLanzhouChina
  2. 2.State Key Laboratory of Applied Organic Chemistry and Department of ChemistryLanzhou UniversityLanzhouChina

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