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Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches

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Drug Target miRNA

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1517))

Abstract

MicroRNA (miRNA) and Argonaute (AGO) protein together form the RNA-induced silencing complex (RISC) that plays an essential role in the regulation of gene expression. Elucidating the underlying mechanism of AGO-miRNA recognition is thus of great importance not only for the in-depth understanding of miRNA function but also for inspiring new drugs targeting miRNAs. In this chapter we introduce a combined computational approach of molecular dynamics (MD) simulations, Markov state models (MSMs), and protein-RNA docking to investigate AGO-miRNA recognition. Constructed from MD simulations, MSMs can elucidate the conformational dynamics of AGO at biologically relevant timescales. Protein-RNA docking can then efficiently identify the AGO conformations that are geometrically accessible to miRNA. Using our recent work on human AGO2 as an example, we explain the rationale and the workflow of our method in details. This combined approach holds great promise to complement experiments in unraveling the mechanisms of molecular recognition between large, flexible, and complex biomolecules.

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Acknowledgment

This work is supported by the Hong Kong Research Grant Council [grant numbers 16302214, 609813, HKUST C6009-15G, AoE/M-09/12, M-HKUST601/13, and T13-607/12R to X.H.] and the National Science Foundation of China [grant number 21273188 to X.H.]. The work is also supported by a grant from the PROCORE-France/Hong Kong Joint Research Scheme sponsored by the Research Grants Council and the Consulate General of France in Hong Kong (F-HK29/11T) (X.H. and J.B.). X.G. was supported by funding from King Abdullah University of Science and Technology. This research made use of the resources of the Supercomputing Laboratory at King Abdullah University of Science and Technology.

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Authors and Affiliations

  1. Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Xuhui Huang

  2. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Lizhe Zhu & Xuhui Huang

  3. Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Lizhe Zhu & Xuhui Huang

  4. Inria Saclay-Île de France, 1 rue Honoré d’Estienne d’Orves, Bâtiment Alan Turing Campus de l’, École Polytechnique, Palaiseau, 91120, France

    Amélie Héliou & Julie Bernauer

  5. Laboratoire d’Informatique de l’École Polytechnique (LIX), CNRS UMR 7161, École Polytechnique, Palaiseau, 91128, France

    Amélie Héliou & Julie Bernauer

  6. King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal, 23955-6900, Saudi Arabia

    Xin Gao

  7. Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, Washington, 98195, USA

    Hanlun Jiang

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  1. Hanlun Jiang
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  2. Lizhe Zhu
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  3. Amélie Héliou
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  4. Xin Gao
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  5. Julie Bernauer
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  6. Xuhui Huang
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Corresponding authors

Correspondence to Xin Gao , Julie Bernauer or Xuhui Huang .

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  1. BEROCEUTICA GmbH, Potsdam, Germany

    Marco F. Schmidt

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Jiang, H., Zhu, L., Héliou, A., Gao, X., Bernauer, J., Huang, X. (2017). Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches. In: Schmidt, M. (eds) Drug Target miRNA. Methods in Molecular Biology, vol 1517. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6563-2_18

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  • DOI: https://doi.org/10.1007/978-1-4939-6563-2_18

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