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PLoS One. 2013;8(1):e54620. doi: 10.1371/journal.pone.0054620. Epub 2013 Jan 29.

Large domain motions in Ago protein controlled by the guide DNA-strand seed region determine the Ago-DNA-mRNA complex recognition process.

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Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, New York, USA.

Erratum in

  • PLoS One. 2013;8(8). doi:10.1371/annotation/dc754ef5-000d-4362-be14-e8b04d5e77e1.


The recognition mechanism and cleavage activity of argonaute (Ago), miRNA, and mRNA complexes are the core processes to the small non-coding RNA world. The 5' nucleation at the 'seed' region (position 2-8) of miRNA was believed to play a significant role in guiding the recognition of target mRNAs to the given miRNA family. In this paper, we have performed all-atom molecular dynamics simulations of the related and recently revealed Ago-DNA:mRNA ternary complexes to study the dynamics of the guide-target recognition and the effect of mutations by introducing "damaging" C·C mismatches at different positions in the seed region of the DNA-RNA duplex. Our simulations show that the A-form-like helix duplex gradually distorts as the number of seed mismatches increases and the complex can survive no more than two such mismatches. Severe distortions of the guide-target heteroduplex are observed in the ruinous 4-sites mismatch mutant, which give rise to a bending motion of the PAZ domain along the L1/L2 "hinge-like" connection segment, resulting in the opening of the nucleic-acid-binding channel. These long-range interactions between the seed region and PAZ domain, moderated by the L1/L2 segments, reveal the central role of the seed region in the guide-target strands recognition: it not only determines the guide-target heteroduplex's nucleation and propagation, but also regulates the dynamic motions of Ago domains around the nucleic-acid-binding channel.

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