title: Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches.
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.
authors.affiliation: Graduate Program in Biological Physics, Structure and Design, University of Washington, Seattle, Washington, 98195, USA.
authors.forename: Hanlun
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.|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.
authors.forename: Lizhe
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Inria Saclay-Île de France, 1 rue Honoré d'Estienne d'Orves, Bâtiment Alan Turing Campus de l', École Polytechnique, Palaiseau, 91120, France.|Laboratoire d'Informatique de l'École Polytechnique (LIX), CNRS UMR 7161, École Polytechnique, Palaiseau, 91128, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Héliou
authors.affiliation: 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@kaust.edu.sa.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Inria Saclay-Île de France, 1 rue Honoré d'Estienne d'Orves, Bâtiment Alan Turing Campus de l', École Polytechnique, Palaiseau, 91120, France. julie.bernauer@inria.fr.|Laboratoire d'Informatique de l'École Polytechnique (LIX), CNRS UMR 7161, École Polytechnique, Palaiseau, 91128, France. julie.bernauer@inria.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Bernauer
authors.affiliation: Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. xuhuihuang@ust.hk.|Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. xuhuihuang@ust.hk.|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. xuhuihuang@ust.hk.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Huang
mesh_terms: D060565:Argonaute Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs
keywords: Argonaute; Markov state model; Molecular dynamics; Molecular recognition; Protein-RNA docking; miRNA