RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction
Thermodynamic folding algorithms and structure probing experiments are commonly used to determine the secondary structure of RNAs. Here we propose a formal framework to reconcile information from both prediction algorithms and probing experiments. The thermodynamic energy parameters are adjusted usi...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | en_US |
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Oxford University Press
2012
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| Online Access: | http://hdl.handle.net/1721.1/73037 |
| _version_ | 1811074850752561152 |
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| author | Mag Washietl, Stefan Hofacker, Ivo L. Stadler, Peter F. Kellis, Manolis |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Mag Washietl, Stefan Hofacker, Ivo L. Stadler, Peter F. Kellis, Manolis |
| author_sort | Mag Washietl, Stefan |
| collection | MIT |
| description | Thermodynamic folding algorithms and structure probing experiments are commonly used to determine the secondary structure of RNAs. Here we propose a formal framework to reconcile information from both prediction algorithms and probing experiments. The thermodynamic energy parameters are adjusted using ‘pseudo-energies’ to minimize the discrepancy between prediction and experiment. Our framework differs from related approaches that used pseudo-energies in several key aspects. (i) The energy model is only changed when necessary and no adjustments are made if prediction and experiment are consistent. (ii) Pseudo-energies remain biophysically interpretable and hold positional information where experiment and model disagree. (iii) The whole thermodynamic ensemble of structures is considered thus allowing to reconstruct mixtures of suboptimal structures from seemingly contradicting data. (iv) The noise of the energy model and the experimental data is explicitly modeled leading to an intuitive weighting factor through which the problem can be seen as folding with ‘soft’ constraints of different strength. We present an efficient algorithm to iteratively calculate pseudo-energies within this framework and demonstrate how this approach can be used in combination with SHAPE chemical probing data to improve secondary structure prediction. We further demonstrate that the pseudo-energies correlate with biophysical effects that are known to affect RNA folding such as chemical nucleotide modifications and protein binding. |
| first_indexed | 2024-09-23T09:56:24Z |
| format | Article |
| id | mit-1721.1/73037 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:56:24Z |
| publishDate | 2012 |
| publisher | Oxford University Press |
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| spelling | mit-1721.1/730372022-09-30T17:49:58Z RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction Mag Washietl, Stefan Hofacker, Ivo L. Stadler, Peter F. Kellis, Manolis Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Kellis, Manolis Mag Washietl, Stefan Kellis, Manolis Thermodynamic folding algorithms and structure probing experiments are commonly used to determine the secondary structure of RNAs. Here we propose a formal framework to reconcile information from both prediction algorithms and probing experiments. The thermodynamic energy parameters are adjusted using ‘pseudo-energies’ to minimize the discrepancy between prediction and experiment. Our framework differs from related approaches that used pseudo-energies in several key aspects. (i) The energy model is only changed when necessary and no adjustments are made if prediction and experiment are consistent. (ii) Pseudo-energies remain biophysically interpretable and hold positional information where experiment and model disagree. (iii) The whole thermodynamic ensemble of structures is considered thus allowing to reconstruct mixtures of suboptimal structures from seemingly contradicting data. (iv) The noise of the energy model and the experimental data is explicitly modeled leading to an intuitive weighting factor through which the problem can be seen as folding with ‘soft’ constraints of different strength. We present an efficient algorithm to iteratively calculate pseudo-energies within this framework and demonstrate how this approach can be used in combination with SHAPE chemical probing data to improve secondary structure prediction. We further demonstrate that the pseudo-energies correlate with biophysical effects that are known to affect RNA folding such as chemical nucleotide modifications and protein binding. Austrian Science Fund. Erwin Schrodinger Fellowship (J2966-B12) 2012-09-18T15:29:29Z 2012-09-18T15:29:29Z 2012-01 2011-12 Article http://purl.org/eprint/type/JournalArticle 0305-1048 1362-4962 http://hdl.handle.net/1721.1/73037 Washietl, S. et al. “RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction.” Nucleic Acids Research 40.10 (2012): 4261–4272. en_US http://dx.doi.org/ 10.1093/nar/gks009 Nucleic Acids Research Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Oxford University Press Nucleic Acids Res. |
| spellingShingle | Mag Washietl, Stefan Hofacker, Ivo L. Stadler, Peter F. Kellis, Manolis RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction |
| title | RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction |
| title_full | RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction |
| title_fullStr | RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction |
| title_full_unstemmed | RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction |
| title_short | RNA Folding with Soft Constraints: Reconciliation of Probing Data and Thermodynamic Secondary Structure Prediction |
| title_sort | rna folding with soft constraints reconciliation of probing data and thermodynamic secondary structure prediction |
| url | http://hdl.handle.net/1721.1/73037 |
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