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Constructing RNA dynamical ensembles by combining MD and motionally decoupled NMR RDCs: new insights into RNA dynamics and adaptive ligand recognition.

Publication ,  Journal Article
Frank, AT; Stelzer, AC; Al-Hashimi, HM; Andricioaei, I
Published in: Nucleic Acids Res
June 2009

We describe a strategy for constructing atomic resolution dynamical ensembles of RNA molecules, spanning up to millisecond timescales, that combines molecular dynamics (MD) simulations with NMR residual dipolar couplings (RDC) measured in elongated RNA. The ensembles are generated via a Monte Carlo procedure by selecting snap-shot from an MD trajectory that reproduce experimentally measured RDCs. Using this approach, we construct ensembles for two variants of the transactivation response element (TAR) containing three (HIV-1) and two (HIV-2) nucleotide bulges. The HIV-1 TAR ensemble reveals significant mobility in bulge residues C24 and U25 and to a lesser extent U23 and neighboring helical residue A22 that give rise to large amplitude spatially correlated twisting and bending helical motions. Omission of bulge residue C24 in HIV-2 TAR leads to a significant reduction in both the local mobility in and around the bulge and amplitude of inter-helical bending motions. In contrast, twisting motions of the helices remain comparable in amplitude to HIV-1 TAR and spatial correlations between them increase significantly. Comparison of the HIV-1 TAR dynamical ensemble and ligand bound TAR conformations reveals that several features of the binding pocket and global conformation are dynamically preformed, providing support for adaptive recognition via a 'conformational selection' type mechanism.

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Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

June 2009

Volume

37

Issue

11

Start / End Page

3670 / 3679

Location

England

Related Subject Headings

  • RNA, Viral
  • Nucleic Acid Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Motion
  • Models, Molecular
  • Ligands
  • HIV-1
  • HIV Long Terminal Repeat
  • Developmental Biology
  • Computer Simulation
 

Citation

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Frank, A. T., Stelzer, A. C., Al-Hashimi, H. M., & Andricioaei, I. (2009). Constructing RNA dynamical ensembles by combining MD and motionally decoupled NMR RDCs: new insights into RNA dynamics and adaptive ligand recognition. Nucleic Acids Res, 37(11), 3670–3679. https://doi.org/10.1093/nar/gkp156
Frank, Aaron T., Andrew C. Stelzer, Hashim M. Al-Hashimi, and Ioan Andricioaei. “Constructing RNA dynamical ensembles by combining MD and motionally decoupled NMR RDCs: new insights into RNA dynamics and adaptive ligand recognition.Nucleic Acids Res 37, no. 11 (June 2009): 3670–79. https://doi.org/10.1093/nar/gkp156.
Frank, Aaron T., et al. “Constructing RNA dynamical ensembles by combining MD and motionally decoupled NMR RDCs: new insights into RNA dynamics and adaptive ligand recognition.Nucleic Acids Res, vol. 37, no. 11, June 2009, pp. 3670–79. Pubmed, doi:10.1093/nar/gkp156.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

June 2009

Volume

37

Issue

11

Start / End Page

3670 / 3679

Location

England

Related Subject Headings

  • RNA, Viral
  • Nucleic Acid Conformation
  • Nuclear Magnetic Resonance, Biomolecular
  • Motion
  • Models, Molecular
  • Ligands
  • HIV-1
  • HIV Long Terminal Repeat
  • Developmental Biology
  • Computer Simulation