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

Hanlun Jiang (1) , Lizhe Zhu (2) , Amélie Héliou (3, 4) , Xin Gao (5) , Julie Bernauer (4, 3) , Xuhui Huang (2)

1 University of Washington [Seattle]
2 HKUST - Hong Kong University of Science and Technology
3 LIX - Laboratoire d'informatique de l'École polytechnique [Palaiseau]
4 AMIB - Algorithms and Models for Integrative Biology
5 KAUST - King Abdullah University of Science and Technology [Saudi Arabia]

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.

Mots clés: miRNA; Argonaute; Molecular recognition; Molecular dynamics; Markov state model; Protein-RNA docking

Domaines: Biologie moléculaire

Hanlun Jiang, Lizhe Zhu, Amélie Héliou, Xin Gao, Julie Bernauer, et al.. Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches. Drug Target miRNA: Methods and Protocols, pp.251--275, 2016, 978-1-4939-6563-2. ⟨10.1007/978-1-4939-6563-2_18⟩. ⟨hal-01569854⟩