Zuber Jeffrey, Sun Hongying, Zhang Xiaoju, McFadyen Iain, Mathews David H
Department of Biochemistry & Biophysics and Center for RNA Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Computational Sciences, Moderna Therapeutics, Cambridge, MA 02141, USA.
Nucleic Acids Res. 2017 Jun 2;45(10):6168-6176. doi: 10.1093/nar/gkx170.
Nearest neighbor parameters for estimating the folding energy changes of RNA secondary structures are used in structure prediction and analysis. Despite their widespread application, a comprehensive analysis of the impact of each parameter on the precision of calculations had not been conducted. To identify the parameters with greatest impact, a sensitivity analysis was performed on the 291 parameters that compose the 2004 version of the free energy nearest neighbor rules. Perturbed parameter sets were generated by perturbing each parameter independently. Then the effect of each individual parameter change on predicted base-pair probabilities and secondary structures as compared to the standard parameter set was observed for a set of sequences including structured ncRNA, mRNA and randomized sequences. The results identify for the first time the parameters with the greatest impact on secondary structure prediction, and the subset which should be prioritized for further study in order to improve the precision of structure prediction. In particular, bulge loop initiation, multibranch loop initiation, AU/GU internal loop closure and AU/GU helix end parameters were particularly important. An analysis of parameter usage during folding free energy calculations of stochastic samples of secondary structures revealed a correlation between parameter usage and impact on structure prediction precision.
用于估计RNA二级结构折叠能量变化的最近邻参数被用于结构预测和分析。尽管它们被广泛应用，但尚未对每个参数对计算精度的影响进行全面分析。为了确定影响最大的参数，对构成2004版自由能最近邻规则的291个参数进行了敏感性分析。通过独立扰动每个参数生成扰动参数集。然后，对于一组包括结构化非编码RNA、信使核糖核酸和随机序列的序列，观察与标准参数集相比，每个单独参数变化对预测碱基对概率和二级结构的影响。结果首次确定了对二级结构预测影响最大的参数，以及为提高结构预测精度应优先进行进一步研究的子集。特别是，凸起环起始、多分支环起始、AU/GU内环闭合和AU/GU螺旋末端参数尤为重要。对二级结构随机样本折叠自由能计算过程中参数使用情况的分析揭示了参数使用与对结构预测精度影响之间的相关性。
