Predicting RNA folding thermodynamics with a reduced chain representation model
Predicting RNA folding thermodynamics with a reduced chain representation model
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作者：
Cao, S;Chen, SJ
基于核苷酸主链的虚拟键表示，我们开发了RNA的简化构象模型。我们使用实验测量的原子坐标来模拟螺旋，并使用金刚石晶格中的自回避行走来模拟环路构象。螺旋的原子坐标和环的晶格表示在环-螺旋连接处匹配，在那里考虑了空间活力。与以往简化的基于晶格的模型不同，目前的虚拟键模型可以解释现实的三维RNA结构的原子细节。基于该模型，我们建立了RNA折叠能量景观和折叠热力学的统计力学理论。实验结果表明，该理论对天然结构、热变性曲线和平衡折叠/展开路径的预测比以往的模型有更大的改进。将该模型应用于四膜虫I族核酶的P5abc区，揭示了平衡折叠过程中的错误折叠中间体和原生样中间体。此外，基于对每个环突变的自由能格局分析，该模型预测了五种致命突变，这些突变可以完全改变分子的自由能格局和折叠稳定性。
Based on the virtual bond representation for the nucleotide backbone, we develop a reduced conformational model for RNA. We use the experimentally measured atomic coordinates to model the helices and use the self-avoiding walks in a diamond lattice to model the loop conformations. The atomic coordinates of the helices and the lattice representation for the loops are matched at the loop-helix junction, where steric viability is accounted for. Unlike the previous simplified lattice-based models, the present virtual bond model can account for the atomic details of realistic three-dimensional RNA structures. Based on the model, we develop a statistical mechanical theory for RNA folding energy landscapes and folding thermodynamics. Tests against experiments show that the theory can give much more improved predictions for the native structures, the thermal denaturation curves, and the equilibrium folding/unfolding pathways than the previous models. The application of the model to the P5abc region of Tetrahymena group I ribozyme reveals the misfolded intermediates as well as the native-like intermediates in the equilibrium folding process. Moreover, based on the free energy landscape analysis for each and every loop mutation, the model predicts five lethal mutations that can completely alter the free energy landscape and the folding stability of the molecule.