期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 90, 期 5, 页码 753-763出版社
WILEY
DOI: 10.1111/cbdd.12997
关键词
conformational changes; human Argonaute 2; molecular dynamics simulation; RNA silencing
资金
- National Natural Science Foundation of China [81603152, 11647146]
- Industry-Academia Cooperation Innovation Fund Project of Jiangsu Province [BY2016030-11, BY2016030-06]
- Six Talent Peaks Project in Jiangsu Province [2016-XYDXXJS-020]
- Applied Basic Study of Changzhou [CJ20160044]
- Qing Lan Project from Educational Committee of Jiangsu Province [16KJD310001]
- University Science Research Project from Educational Committee of Jiangsu Province [16KJD310001]
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund
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.
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