Native-like RNA tertiary structures using a sequence-encoded cleavage agent and refinement by discrete molecular dynamics

Costin M. Gherghe, Christopher W. Leonard, Feng Ding, Nikolay V. Dokholyan, Kevin M. Weeks

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The difficulty of analyzing higher order RNA structure, especially for folding intermediates and for RNAs whose functions require domains that are conformationally flexible, emphasizes the need for new approaches for modeling RNA tertiary structure accurately. Here, we report a concise approach that makes use of facile RNA structure probing experiments that are then interpreted using a computational algorithm, carefully tailored to optimize both the resolution and refinement speed for the resulting structures, without requiring user intervention. The RNA secondary structure is first established using SHAPE chemistry. We then use a sequence-directed cleavage agent, which can be placed arbitrarily in many helical motifs, to obtain high quality inter-residue distances. We interpret this in-solution chemical information using a fast, coarse grained, discrete molecular dynamics engine in which each RNA nucleotide is represented by pseudoatoms for the phosphate, ribose, and nucleobase groups. By this approach, we refine base paired positions in yeast tRNA Asp to 4 Å rmsd without any preexisting information or assumptions about secondary or tertiary structures. This blended experimental and computational approach has the potential to yield native-like models for the diverse universe of functionally important RNAs whose structures cannot be characterized by conventional structural methods.

Original languageEnglish (US)
Pages (from-to)2541-2546
Number of pages6
JournalJournal of the American Chemical Society
Volume131
Issue number7
DOIs
StatePublished - Feb 25 2009

Fingerprint

Molecular Dynamics Simulation
RNA
Molecular dynamics
RNA, Transfer, Asp
RNA Folding
Ribose
Nucleotides
Yeast
Yeasts
Phosphates
Engines
Experiments

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry
  • Medicine(all)

Cite this

Gherghe, Costin M. ; Leonard, Christopher W. ; Ding, Feng ; Dokholyan, Nikolay V. ; Weeks, Kevin M. / Native-like RNA tertiary structures using a sequence-encoded cleavage agent and refinement by discrete molecular dynamics. In: Journal of the American Chemical Society. 2009 ; Vol. 131, No. 7. pp. 2541-2546.
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Native-like RNA tertiary structures using a sequence-encoded cleavage agent and refinement by discrete molecular dynamics. / Gherghe, Costin M.; Leonard, Christopher W.; Ding, Feng; Dokholyan, Nikolay V.; Weeks, Kevin M.

In: Journal of the American Chemical Society, Vol. 131, No. 7, 25.02.2009, p. 2541-2546.

Research output: Contribution to journalArticle

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