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Indexed by:期刊论文

Date of Publication:2012-08-01

Journal:JOURNAL OF MOLECULAR MODELING

Included Journals:SCIE、Scopus

Volume:18

Issue:8

Page Number:3769-3781

ISSN No.:1610-2940

Key Words:Argonaute; Mg2+; MiRNA-mRNA; MM/GBSA; Molecular dynamic simulation

Abstract:Three magnesium ions (Mg2+), named Mg1 (in Mid domain), Mg2 and Mg3 (both in PIWI domain), located at the small RNA binding domain of Argonaute (Ago) protein, are important for sequence-specific miRNA-target interactions. Such conjunction between the Ago protein and miRNA raises the question: How do Mg2+ ions participate in the recognition process of miRNA by Ago or its target. Furthermore, it is still unclear whether the Mg2+ ions contribute to the local or global stability of the miRNA complex. In this work, we have performed a series of 16 independent molecular dynamic simulations (MD) to characterize the functions of Mg2+, hydration patterns and the conformational events involved in the miRNA-target interactions. The cross correlation analysis shows that Mg1 and Mg2 significantly enhance a locally cooperated movement of the PAZ, PIWI and Mid domains with the average correlation coefficient of similar to 0.65, producing an "open-closed" motion (rotation Angle, 46.5A degrees) between the PAZ and PIWI domains. Binding of Mg3 can globally stabilize the whole Ago protein with the average RMSD of similar to 0.34 , compared with the systems in absence of Mg3 (average RMSD = similar to 0.43 ). Three structural water molecules surrounding the Mg2+-binding regions also stabilize these ions, thus facilitating the recognition of miRNA to its target. In addition, the thermodynamic analysis also verifies the positive contribution of all three Mg2+ to the binding of miRNA to Ago, as well as the importance Mg2 plays in the cleavage of the miRNA targets.