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Accurate SHAPE-directed RNA secondary structure modeling, including pseudoknots

Hajdin, Christine E., Bellaousov, Stanislav, Huggins, Wayne, Leonard, Christopher W., Mathews, David H., Weeks, Kevin M.
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.14 pp. 5498-5503
RNA, acylation, algorithms, dynamic programming, energy, models, nucleotides, prediction, regulatory sequences, thermodynamics, viruses
A pseudoknot forms in an RNA when nucleotides in a loop pair with a region outside the helices that close the loop. Pseudoknots occur relatively rarely in RNA but are highly overrepresented in functionally critical motifs in large catalytic RNAs, in riboswitches, and in regulatory elements of viruses. Pseudoknots are usually excluded from RNA structure prediction algorithms. When included, these pairings are difficult to model accurately, especially in large RNAs, because allowing this structure dramatically increases the number of possible incorrect folds and because it is difficult to search the fold space for an optimal structure. We have developed a concise secondary structure modeling approach that combines SHAPE (selective 2′-hydroxyl acylation analyzed by primer extension) experimental chemical probing information and a simple, but robust, energy model for the entropic cost of single pseudoknot formation. Structures are predicted with iterative refinement, using a dynamic programming algorithm. This melded experimental and thermodynamic energy function predicted the secondary structures and the pseudoknots for a set of 21 challenging RNAs of known structure ranging in size from 34 to 530 nt. On average, 93% of known base pairs were predicted, and all pseudoknots in well-folded RNAs were identified.