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Nucleic Acids Research, 2002, Vol. 30, No. 16 3574-3582
© 2002 Oxford University Press

RNA molecules with structure dependent functions are uniquely folded

Shu-Yun Le*, Kaizhong Zhang1 and Jacob V. Maizel Jr

Laboratory of Experimental and Computational Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Building 469, Room 151, Frederick, MD 21702, USA and 1 Department of Computer Science, University of Western Ontario, London, ON N6A 5B7, Canada

*To whom correspondence should be addressed. Tel: +1 301 846 5576; Fax: +1 301 846 5598; Email: shuyun{at}orleans.ncifcrf.gov

Cis-acting elements in post-transcriptional regulation of gene expression are often correlated with distinct local RNA secondary structure. These structures are expected to be significantly more ordered than those anticipated at random because of evolutionary constraints and intrinsic structural properties. In this study, we introduce a computing method to calculate two quantitative measures, NRd and Stscr, for estimating the uniqueness of an RNA secondary structure. NRd is a normalized score based on evaluating how different a natural RNA structure is from those predicted for its randomly shuffled variants. The lower the score NRd the more well ordered is the natural RNA structure. The statistical significance of NRd compared with that computed from structural comparisons among large numbers of randomly permuted sequences is represented by a standardized score, Stscr. We tested the method on the trans-activation response element and Rev response element of HIV-1 mRNA, internal ribosome entry sequence of hepatitis C virus, Tetrahymena thermophila rRNA intron, 100 tRNAs and 14 RNase P RNAs. Our data indicate that functional RNA structures have high Stscr, while other structures have low Stscr. We conclude that RNA functional molecules and/or cis-acting elements with structure dependent functions possess well ordered conformations and they are uniquely folded as measured by this technique.


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