title: Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement.
abstract: Argonaute (Ago) proteins and microRNAs (miRNAs) are central components in RNA interference, which is a key cellular mechanism for sequence-specific gene silencing. Despite intensive studies, molecular mechanisms of how Ago recognizes miRNA remain largely elusive. In this study, we propose a two-step mechanism for this molecular recognition: selective binding followed by structural re-arrangement. Our model is based on the results of a combination of Markov State Models (MSMs), large-scale protein-RNA docking, and molecular dynamics (MD) simulations. Using MSMs, we identify an open state of apo human Ago-2 in fast equilibrium with partially open and closed states. Conformations in this open state are distinguished by their largely exposed binding grooves that can geometrically accommodate miRNA as indicated in our protein-RNA docking studies. miRNA may then selectively bind to these open conformations. Upon the initial binding, the complex may perform further structural re-arrangement as shown in our MD simulations and eventually reach the stable binary complex structure. Our results provide novel insights in Ago-miRNA recognition mechanisms and our methodology holds great potential to be widely applied in the studies of other important molecular recognition systems.
authors.affiliation: Bioengineering Graduate Program, Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; The HKUST Shenzhen Research Institute, Shenzhen, China.
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.
authors.forename: Fu Kit
authors.initials: FK
authors.lastname: Sheong
authors.affiliation: The HKUST Shenzhen Research Institute, Shenzhen, China; Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; 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.
authors.forename: Lizhe
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Inria Saclay-Île de France, Bâtiment Alan Turing, Campus de l'École Polytechnique, Palaiseau, France; Laboratoire d'Informatique de l'École Polytechnique (LIX), CNRS UMR 7161, École Polytechnique, Palaiseau, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bernauer
authors.affiliation: Bioengineering Graduate Program, Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; The HKUST Shenzhen Research Institute, Shenzhen, China; Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; 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.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Huang
mesh_terms: D060565:Argonaute Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D006801:Humans; D008390:Markov Chains; D035683:MicroRNAs / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D015233:Models, Statistical; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs