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Journal of Computer-Aided Molecular Design

, Volume 26, Issue 7, pp 865–881 | Cite as

Understanding the molecular interactions of different radical scavengers with ribonucleotide reductase M2 (hRRM2) domain: opening the gates and gaining access

  • Arijit Basu
  • Barij N. Sinha
Article
  • 183 Downloads

Abstract

We employed a combination of molecular docking and dynamics to understand the interaction of three different radical scavengers (SB-HSC21, ABNM13 and trimidox) with ribonucleotide reductase M2 (hRRM2) domain. On the basis of the observed results, we can propose how these ligands interact with the enzyme, and cease the radical transfer step from the di-iron center to TYR176. All the ligands alter the electron density over TYR176, –OH group by forming an extremely stable H-bond with either –NHOH group, or with phenolic hydroxyl group of the ligands. This change in electronic density disrupts the water bridge between TYR176, –OH and the di-iron center, which stops the single electron transfer process from TYR176, –OH to iron. As a consequence the enzyme is inhibited. Another interesting observation that we are reporting is the two stage gate keeping mechanism of the RR active site tunnel. We describe these as the outer Gate-1 controlled by ARG330, and the inner Gate-2 controlled by SER263, PHE240, and PHE236. We also observed a dynamic conformational shift in these residues, the incoming ligands can go through, and interact with the underlying TYR176, –OH group. From the study we found the active—site of hRRM2 is extremely flexible and shows a significant induced fit.

Keywords

Molecular dynamics Ribonucleotide reductase (RR) Gate keeper residues Molecular docking 

Notes

Acknowledgments

We thank University Grants Commission for providing necessary financial support for the current work. We also thank Mrs. Nibha Mishra and Dr. Venkatesan J for proofreading our manuscript.

Supplementary material

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Supplementary material 1 (DOC 534 kb)
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Supplementary material 2 (DOC 534 kb)
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Supplementary material 3 (DOC 534 kb)
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Supplementary material 4 (DOC 535 kb)

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesBirla Institute of TechnologyRanchiIndia

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