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Nucleic Acids Research Advance Access published online on November 6, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn871
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

A rugged free energy landscape separates multiple functional RNA folds throughout denaturation

Mark A. Ditzler1,2, David Rueda2, Jingjie Mo2, Kristina Håkansson2 and Nils G. Walter2,*

1Department of Biophysics and 2Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA

*To whom correspondence should be addressed. Tel: +1 734 615 2060; Fax: +1 734 647 4865; Email: nwalter{at}umich.edu

Received August 13, 2008. Revised September 25, 2008. Accepted October 18, 2008.

The dynamic mechanisms by which RNAs acquire biologically functional structures are of increasing importance to the rapidly expanding fields of RNA therapeutics and biotechnology. Large energy barriers separating misfolded and functional states arising from alternate base pairing are a well-appreciated characteristic of RNA. In contrast, it is typically assumed that functionally folded RNA occupies a single native basin of attraction that is free of deeply dividing energy barriers (ergodic hypothesis). This assumption is widely used as an implicit basis to interpret experimental ensemble-averaged data. Here, we develop an experimental approach to isolate persistent sub-populations of a small RNA enzyme and show by single molecule fluorescence resonance energy transfer (smFRET), biochemical probing and high-resolution mass spectrometry that commitment to one of several catalytically active folds occurs unexpectedly high on the RNA folding energy landscape, resulting in partially irreversible folding. Our experiments reveal the retention of molecular heterogeneity following the complete loss of all native secondary and tertiary structure. Our results demonstrate a surprising longevity of molecular heterogeneity and advance our current understanding beyond that of non-functional misfolds of RNA kinetically trapped on a rugged folding-free energy landscape.

Present address: David Rueda, Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.


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