Statistical Mechanics of RNA Folding

描述（由申请人提供）：一个准确的RNA三级折叠模型的可用性可以极大地帮助我们理解RNA的功能和RNA靶向药物的发现。然而，与已经被广泛研究了几十年的蛋白质折叠问题不同，三级RNA折叠的建模是一个相对较新的领域。我们目前的图论热力学模型使我们能够比其他现有的模型更好地预测RNA二级结构的熔化曲线。在这个提议中，我们的目标是超越二级结构模型来研究三级RNA折叠。我们的方法的一个关键优势是我们的构象采样的完整性和确定性。不完整的构象取样可能导致不可接受的精度损失。我们的热力学和动力学模型将在这个项目中并行发展。由用户提供能量参数的热力学模型将使我们能够从实验熔化曲线中提取RNA三级相互作用的参数。自第一次提交该提案以来，我们已经产生了新的结果，表明我们可以准确地捕获第三纪褶皱和离晶格构象，以给出可靠的配分函数。动力学模型将使用主方程方法开发，我们已经成功地用于处理RNA发夹折叠动力学。我们的长期目标是超越发夹疗法来治疗大型复杂rna。我们的近期目标是在实现长期目标的道路上消除两个关键的“障碍”：从速率方程中搜索过渡态，并通过构象聚类减少速率方程。实验测试将集中在一系列合理设计的RNA系统上。关键的一点是，实验将在与理论预测完全相同的盐条件下进行。

DESCRIPTION (provided by applicant): The availability of an accurate model for RNA tertiary folding can greatly aid in our understanding of RNA functions and in RNA-targeted drug discovery. However, unlike the protein folding problem which has been extensively studied for decades, modeling of tertiary RNA folding is a relatively new field of endeavor. Our current graph-theoretic thermodynamic model has allowed us to make better predictions than other existing models on RNA secondary structure melting curves. In this proposal, we aim to move beyond the secondary structure model to study tertiary RNA folding. A key advantage of our approach is the completeness and certainty in our conformational sampling. Incomplete conformational sampling may result in unacceptable loss of accuracy. Our thermodynamic and kinetic models will be developed in parallel in this project. The thermodynamic model, in which user can supply energy parameters, will enable us to extract parameters for RNA tertiary interactions from experimental melting curves. Since the first submission of this proposal, we have generated new results indicating that we can accurately capture tertiary folds and off-lattice conformations to give reliable partition functions. The kinetic model will be developed using a master equation approach, which we have successfully used to treat RNA hairpin folding kinetics. Our long-term goal is to move beyond hairpin to treat large complex RNAs. Our immediate goal is to remove two key "roadblocks" on the road toward our long-term goal: to search for transition states from rate equations, and to reduce the rate equations by conformational clustering. Experimental tests will focus on a series of rationally designed RNA systems. A key point is that the experiments will be performed under exactly the same salt condition used in theoretical predictions.