Mg2+ effect on argonaute and RNA duplex by molecular dynamics and bioinformatics implications

Seungyoon Nam, Hyojung Ryu, Won Joon Son, Yon Hui Kim, Kyung Tae Kim, Curt Balch, Kenneth Nephew, Jinhyuk Lee

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

RNA interference (RNAi), mediated by small non-coding RNAs (e.g., miRNAs, siRNAs), influences diverse cellular functions. Highly complementary miRNA-target RNA (or siRNA-target RNA) duplexes are recognized by an Argonaute family protein (Ago2), and recent observations indicate that the concentration of Mg2+ ions influences miRNA targeting of specific mRNAs, thereby modulating miRNA-mRNA networks. In the present report, we studied the thermodynamic effects of differential [Mg2+] on slicing (RNA silencing cycle) through molecular dynamics simulation analysis, and its subsequent statistical analysis. Those analyses revealed different structural conformations of the RNA duplex in Ago2, depending on Mg2+ concentration. We also demonstrate that cation effects on Ago2 structural flexibility are critical to its catalytic/functional activity, with low [Mg2+] favoring greater Ago2 flexibility (e.g., greater entropy) and less miRNA/mRNA duplex stability, thus favoring slicing. The latter finding was supported by a negative correlation between expression of an Mg2+ influx channel, TRPM7, and one miRNA's (miR-378) ability to downregulate its mRNA target, TMEM245. These results imply that thermodynamics could be applied to siRNA-based therapeutic strategies, using highly complementary binding targets, because Ago2 is also involved in RNAi slicing by exogenous siRNAs. However, the efficacy of a siRNA-based approach will differ, to some extent, based on the Mg2+ concentration even within the same disease type; therefore, different siRNA-based approaches might be considered for patient-to-patient needs.

Original languageEnglish
Article numbere109745
JournalPLoS One
Volume9
Issue number10
DOIs
StatePublished - Oct 17 2014

Fingerprint

molecular dynamics
Molecular Dynamics Simulation
Bioinformatics
Computational Biology
MicroRNAs
microRNA
bioinformatics
Molecular dynamics
small interfering RNA
slicing
RNA
Small Interfering RNA
RNA interference
RNA Interference
Messenger RNA
thermodynamics
Thermodynamics
Argonaute Proteins
Nucleic Acid Conformation
Small Untranslated RNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nam, S., Ryu, H., Son, W. J., Kim, Y. H., Kim, K. T., Balch, C., ... Lee, J. (2014). Mg2+ effect on argonaute and RNA duplex by molecular dynamics and bioinformatics implications. PLoS One, 9(10), [e109745]. https://doi.org/10.1371/journal.pone.0109745

Mg2+ effect on argonaute and RNA duplex by molecular dynamics and bioinformatics implications. / Nam, Seungyoon; Ryu, Hyojung; Son, Won Joon; Kim, Yon Hui; Kim, Kyung Tae; Balch, Curt; Nephew, Kenneth; Lee, Jinhyuk.

In: PLoS One, Vol. 9, No. 10, e109745, 17.10.2014.

Research output: Contribution to journalArticle

Nam, Seungyoon ; Ryu, Hyojung ; Son, Won Joon ; Kim, Yon Hui ; Kim, Kyung Tae ; Balch, Curt ; Nephew, Kenneth ; Lee, Jinhyuk. / Mg2+ effect on argonaute and RNA duplex by molecular dynamics and bioinformatics implications. In: PLoS One. 2014 ; Vol. 9, No. 10.
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