Ab initio RNA folding by discrete molecular dynamics: From structure prediction to folding mechanisms
- Feng Ding1,
- Shantanu Sharma1,
- Poornima Chalasani2,3,
- Vadim V. Demidov2,3,
- Natalia E. Broude2,3, and
- Nikolay V. Dokholyan1
- 1Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
- 2Center for Advanced Biotechnology, Boston University, Boston, Massachusetts 02215, USA
- 3Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA
Abstract
RNA molecules with novel functions have revived interest in the accurate prediction of RNA three-dimensional (3D) structure and folding dynamics. However, existing methods are inefficient in automated 3D structure prediction. Here, we report a robust computational approach for rapid folding of RNA molecules. We develop a simplified RNA model for discrete molecular dynamics (DMD) simulations, incorporating base-pairing and base-stacking interactions. We demonstrate correct folding of 150 structurally diverse RNA sequences. The majority of DMD-predicted 3D structures have <4 Å deviations from experimental structures. The secondary structures corresponding to the predicted 3D structures consist of 94% native base-pair interactions. Folding thermodynamics and kinetics of tRNAPhe, pseudoknots, and mRNA fragments in DMD simulations are in agreement with previous experimental findings. Folding of RNA molecules features transient, non-native conformations, suggesting non-hierarchical RNA folding. Our method allows rapid conformational sampling of RNA folding, with computational time increasing linearly with RNA length. We envision this approach as a promising tool for RNA structural and functional analyses.
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Footnotes
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Reprint requests to: Nikolay V. Dokholyan; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; e-mail: dokh{at}med.unc.edu; fax: (919) 966-2852.
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Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.894608.
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- Received October 29, 2007.
- Accepted March 1, 2008.
- Copyright © 2008 RNA Society