title: Understanding the core of RNA interference: The dynamic aspects of Argonaute-mediated processes.
abstract: At the core of RNA interference, the Argonaute proteins (Ago) load and utilize small guide nucleic acids to silence mRNAs or cleave foreign nucleic acids in a sequence specific manner. In recent years, based on extensive structural studies of Ago and its interaction with the nucleic acids, considerable progress has been made to reveal the dynamic aspects of various Ago-mediated processes. Here we review these novel insights into the guide-strand loading, duplex unwinding, and effects of seed mismatch, with a focus on two representative Agos, the human Ago 2 (hAgo2) and the bacterial Thermus thermophilus Ago (TtAgo). In particular, comprehensive molecular simulation studies revealed that although sharing similar overall structures, the two Agos have vastly different conformational landscapes and guide-strand loading mechanisms because of the distinct rigidity of their L1-PAZ hinge. Given the central role of the PAZ motions in regulating the exposure of the nucleic acid binding channel, these findings exemplify the importance of protein motions in distinguishing the overlapping, yet distinct, mechanisms of Ago-mediated processes in different organisms.
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Center of Systems Biology and Human Health, 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: Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Bioengineering Graduate Program, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
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: King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal, 23955, Saudi Arabia.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Cui
authors.affiliation: Laboratory of Non-Coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wang
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, Saudi Arabia.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Bioengineering Graduate Program, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. Electronic address: Xin.Gao@kaust.edu.sa.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism*; D006801:Humans; D034622:RNA Interference; D016963:Thermus thermophilus / Q000235:genetics / Q000378:metabolism
chemical_list: D060565:Argonaute Proteins
keywords: Argonaute; Enhanced sampling; Kinetics; Markov-state-models; Mechanism; Molecular dynamics simulation; Protein motions; Protein-DNA/RNA docking; RNA interference