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In silico molecular docking analysis of the human Argonaute 2 PAZ domain reveals insights into RNA interference

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Abstract

RNA interference (RNAi) is a critical cellular pathway activated by double stranded RNA and regulates the gene expression of target mRNA. During RNAi, the 3′ end of siRNA binds with the PAZ domain, followed by release and rebinding in a cyclic manner, which deemed essential for proper gene silencing. Recently, we provided the forces underlying the recognition of small interfering RNA by PAZ in a computational study based on the structure of Drosophila Argonaute 2 (Ago2) PAZ domain. We have now reanalyzed these data within the view of the new available structures from human Argonauts. While the parameters of weak binding are correlated with higher (RNAi) in the Drosophila model, a different profile is predicted with the human Ago2 PAZ domain. On the basis of the human Ago2 PAZ models, the indicators of stronger binding as the total binding energy and the free energy were associated with better RNAi efficacy. This discrepancy might be attributable to differences in the binding site topology and the difference in the conformation of the bound nucleotides.

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Acknowledgments

Research support from Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Grants-in-Aid for scientific Research (Grant No. 24390025) from the Japan Society for the Promotion of Science (JSPS).The authors provide that “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript”.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshiekh University, Kafrelshiekh, 33516, Egypt

    Mahmoud Kandeel

  2. Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu, 501-1193, Japan

    Yukio Kitade

  3. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan

    Mahmoud Kandeel & Yukio Kitade

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  1. Mahmoud Kandeel
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  2. Yukio Kitade
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Correspondence to Mahmoud Kandeel or Yukio Kitade.

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Kandeel, M., Kitade, Y. In silico molecular docking analysis of the human Argonaute 2 PAZ domain reveals insights into RNA interference. J Comput Aided Mol Des 27, 605–614 (2013). https://doi.org/10.1007/s10822-013-9665-3

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