RNA folding with soft constraints: reconciliation of probing data and thermodynamic secondary structure prediction.
RNA folding with soft constraints: reconciliation of probing data and thermodynamic secondary structure prediction.
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DOI：
10.1093/nar/gks009
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发表时间：
2012-05
影响因子：
14.9
通讯作者：
Kellis M
中科院分区：
文献类型：
--
作者：
Washietl S;Hofacker IL;Stadler PF;Kellis M
热力学折叠算法和结构探测实验通常用于确定 RNA 的二级结构。在这里，我们提出了一个正式的框架来协调来自预测算法和探测实验的信息。使用“伪能量”调整热力学能量参数，以尽量减少预测与实验之间的差异。我们的框架在几个关键方面不同于使用伪能量的相关方法。 (i) 能量模型仅在必要时改变，如果预测与实验一致则不进行调整。 (ii) 赝能量在生物物理上仍然是可解释的，并且在实验和模型不一致的情况下保留位置信息。 （iii）考虑了结构的整个热力学系综，从而允许从看似矛盾的数据重建次优结构的混合物。 (iv) 能量模型和实验数据的噪声被明确建模，从而产生直观的加权因子，通过该因子可以将问题视为具有不同强度的“软”约束的折叠。我们提出了一种有效的算法来迭代计算该框架内的赝能量，并演示了如何将该方法与 SHAPE 化学探测数据结合使用以改进二级结构预测。我们进一步证明，伪能量与已知影响 RNA 折叠的生物物理效应相关，例如化学核苷酸修饰和蛋白质结合。
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.
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影响因子：
1.8
作者：
HOFACKER, IL;FONTANA, W;SCHUSTER, P
通讯作者：
SCHUSTER, P
影响因子：
2.9
作者：
MCCASKILL, JS
通讯作者：
MCCASKILL, JS
影响因子：
48
作者：
Underwood, Jason G.;Uzilov, Andrew V.;Katzman, Sol;Onodera, Courtney S.;Mainzer, Jacob E.;Mathews, David H.;Lowe, Todd M.;Salama, Sofie R.;Haussler, David
通讯作者：
Haussler, David
影响因子：
2.9
作者：
Motorin, Yuri;Helm, Mark
通讯作者：
Helm, Mark
影响因子：
64.8
作者：
通讯作者：
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