title: Exploring the RNA-bound and RNA-free human Argonaute-2 by molecular dynamics simulation method.
abstract: Argonaute 2 (Ago2) protein is the major vehicle of microRNAs (miRNAs)-guided gene repression and silencing processes. Although the crystal structure of human Ago2 (hAgo2) has recently been disclosed, the information of dynamically structural character of protein-RNA recognition is still lacking. Molecular dynamics simulations were used to systematically explore hAgo2 in the presence and absence of RNA duplex. Stable direct and water-mediated hydrogen bonds were observed between guide RNA backbone atoms and hAgo2, especially for nucleotides 2-7. In addition, water-mediated hydrogen bonds are indicated to be critical in the specific recognition between hAgo2 and the conserved adenine in position 1 of target RNA. The core domains (N, PAZ, MID, and PIWI) possess rigid body movements during the simulations. The motions of N-PAZ and PIWI-MID are negatively correlated with or without RNA binding and PAZ domain is identified as the most mobile domain in both systems. The reorientation of PAZ domain not only influences the binding of helix-7 and RNA duplex, the initial pairing process, but also the shape of N-PAZ cleft, where the supplemental base pairing occurs. It is speculated that PAZ domain could be a key regulator in hAgo2-mediated miRNA-induced gene regulation.
authors.affiliation: School of Electrical and Information Engineering, Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Ren
authors.identifier: http://orcid.org/0000-0001-9010-1750
authors.initials: R
authors.lastname: Kong
authors.affiliation: School of Electrical and Information Engineering, Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: School of Electrical and Information Engineering, Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Lianhua
authors.initials: L
authors.lastname: Piao
authors.affiliation: School of Electrical and Information Engineering, Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Ting-Jun
authors.initials: TJ
authors.lastname: Hou
authors.affiliation: School of Electrical and Information Engineering, Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chang
mesh_terms: D060565:Argonaute Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072417:Protein Domains; D012313:RNA / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D012313:RNA
keywords: RNA silencing; conformational changes; human Argonaute 2; molecular dynamics simulation