Tertiary structure-based analysis of microRNA-target interactions

Hin Hark Gan, Kristin C. Gunsalus

Research output: Contribution to journalArticle

Abstract

Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex-Argonaute protein complexes into a pipeline to model and predict miRNA-target duplex binding energies. To ensure modeling accuracy and computational efficiency, we use an all-atom description of RNA and a continuum description of ionic interactions using the Poisson- Boltzmann equation. Our method predicts the conformations of two constructs of Caenorhabditis elegans let-7 miRNA-target duplexes to an accuracy of ∼3.8 Å root mean square distance of their NMR structures. We also show that the computed duplex formation enthalpies, entropies, and free energies for eight miRNA-target duplexes agree with titration calorimetry data. Analysis of duplex-Argonaute docking shows that structural distortions arising from single-base-pair mismatches in the seed region influence the activity of the complex by destabilizing both duplex hybridization and its association with Argonaute. Collectively, these results demonstrate that tertiary structure-based modeling of miRNA interactions can reveal structural mechanisms not accessible with current secondary structure-based methods.

Original languageEnglish (US)
Pages (from-to)539-551
Number of pages13
JournalRNA
Volume19
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

MicroRNAs
Entropy
Base Pair Mismatch
Argonaute Proteins
RNA
Calorimetry
Caenorhabditis elegans
Osmolar Concentration
Seeds

Keywords

  • Duplex binding free energy
  • Entropy of duplex formation
  • microRNA
  • miRNA tertiary structures
  • miRNA-Argonaute docking

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Tertiary structure-based analysis of microRNA-target interactions. / Gan, Hin Hark; Gunsalus, Kristin C.

In: RNA, Vol. 19, No. 4, 04.2013, p. 539-551.

Research output: Contribution to journalArticle

@article{7a62a185e9dc43d0905a54c103e2e925,
title = "Tertiary structure-based analysis of microRNA-target interactions",
abstract = "Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex-Argonaute protein complexes into a pipeline to model and predict miRNA-target duplex binding energies. To ensure modeling accuracy and computational efficiency, we use an all-atom description of RNA and a continuum description of ionic interactions using the Poisson- Boltzmann equation. Our method predicts the conformations of two constructs of Caenorhabditis elegans let-7 miRNA-target duplexes to an accuracy of ∼3.8 {\AA} root mean square distance of their NMR structures. We also show that the computed duplex formation enthalpies, entropies, and free energies for eight miRNA-target duplexes agree with titration calorimetry data. Analysis of duplex-Argonaute docking shows that structural distortions arising from single-base-pair mismatches in the seed region influence the activity of the complex by destabilizing both duplex hybridization and its association with Argonaute. Collectively, these results demonstrate that tertiary structure-based modeling of miRNA interactions can reveal structural mechanisms not accessible with current secondary structure-based methods.",
keywords = "Duplex binding free energy, Entropy of duplex formation, microRNA, miRNA tertiary structures, miRNA-Argonaute docking",
author = "Gan, {Hin Hark} and Gunsalus, {Kristin C.}",
year = "2013",
month = "4",
doi = "10.1261/rna.035691.112",
language = "English (US)",
volume = "19",
pages = "539--551",
journal = "RNA",
issn = "1355-8382",
publisher = "Cold Spring Harbor Laboratory Press",
number = "4",

}

TY - JOUR

T1 - Tertiary structure-based analysis of microRNA-target interactions

AU - Gan, Hin Hark

AU - Gunsalus, Kristin C.

PY - 2013/4

Y1 - 2013/4

N2 - Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex-Argonaute protein complexes into a pipeline to model and predict miRNA-target duplex binding energies. To ensure modeling accuracy and computational efficiency, we use an all-atom description of RNA and a continuum description of ionic interactions using the Poisson- Boltzmann equation. Our method predicts the conformations of two constructs of Caenorhabditis elegans let-7 miRNA-target duplexes to an accuracy of ∼3.8 Å root mean square distance of their NMR structures. We also show that the computed duplex formation enthalpies, entropies, and free energies for eight miRNA-target duplexes agree with titration calorimetry data. Analysis of duplex-Argonaute docking shows that structural distortions arising from single-base-pair mismatches in the seed region influence the activity of the complex by destabilizing both duplex hybridization and its association with Argonaute. Collectively, these results demonstrate that tertiary structure-based modeling of miRNA interactions can reveal structural mechanisms not accessible with current secondary structure-based methods.

AB - Current computational analysis of microRNA interactions is based largely on primary and secondary structure analysis. Computationally efficient tertiary structure-based methods are needed to enable more realistic modeling of the molecular interactions underlying miRNA-mediated translational repression. We incorporate algorithms for predicting duplex RNA structures, ionic strength effects, duplex entropy and free energy, and docking of duplex-Argonaute protein complexes into a pipeline to model and predict miRNA-target duplex binding energies. To ensure modeling accuracy and computational efficiency, we use an all-atom description of RNA and a continuum description of ionic interactions using the Poisson- Boltzmann equation. Our method predicts the conformations of two constructs of Caenorhabditis elegans let-7 miRNA-target duplexes to an accuracy of ∼3.8 Å root mean square distance of their NMR structures. We also show that the computed duplex formation enthalpies, entropies, and free energies for eight miRNA-target duplexes agree with titration calorimetry data. Analysis of duplex-Argonaute docking shows that structural distortions arising from single-base-pair mismatches in the seed region influence the activity of the complex by destabilizing both duplex hybridization and its association with Argonaute. Collectively, these results demonstrate that tertiary structure-based modeling of miRNA interactions can reveal structural mechanisms not accessible with current secondary structure-based methods.

KW - Duplex binding free energy

KW - Entropy of duplex formation

KW - microRNA

KW - miRNA tertiary structures

KW - miRNA-Argonaute docking

UR - http://www.scopus.com/inward/record.url?scp=84875466989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875466989&partnerID=8YFLogxK

U2 - 10.1261/rna.035691.112

DO - 10.1261/rna.035691.112

M3 - Article

VL - 19

SP - 539

EP - 551

JO - RNA

JF - RNA

SN - 1355-8382

IS - 4

ER -