Predicting ion Effects in RNA Folding

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。当今后基因组时代面临的一个巨大挑战是如何理解隐藏在基因组中的信息。从DNA序列到蛋白质结构的信息解码的关键一步是通过核糖核酸（RNA）分子的功能发生的。RNA的功能取决于其三维结构和稳定性。由于RNA是高电荷的多阴离子，它们的折叠集中了负电荷，这被与RNA的显著离子结合所抵消，使得RNA的结构和稳定性强烈依赖于溶液中的离子效应。许多关于RNA折叠中离子效应的建模研究都是基于平均场泊松-玻尔兹曼方法。这些方法不考虑离子的相关性、波动或有限大小。然而，各种各样的实验已经指出了这三种效应对镁等多价离子的潜在重要性。由于镁离子对RNA三级结构折叠至关重要，因此无法处理相关/波动和离子大小效应，极大地限制了各种应用中对RNA的理解、预测和设计。本项目将通过开发一种新的模型来理解二价离子对RNA结构和功能的重要作用，从而在理论上解决这一缺陷。更广泛的影响：对RNA折叠中离子效应的定量预测将影响广泛的RNA相关研究，包括RNA稳定力的定量，RNA稳定性和折叠协同性的预测，对核酶、核开关和微RNA机制的定量理解，以及治疗性RNA适体的合理设计。该项目将为来自传统物理科学背景的研究生和博士后提供独特的教育和培训机会，使他们能够进入生物物理学领域。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).A great challenge facing today's post-genomic era is how to understand the hidden information buried within genomes. A crucial step in information decoding from DNA sequence to protein structure occurs through the function of the ribonucleic acid (RNA) molecules. The functions of RNA depend on the three-dimensional structure and stability. Because RNAs are highly charged polyanions, their folding concentrates negative charge, which is countered by significant ion binding to the RNA making structure and stability strongly dependent on ion effects in the solution. Many modeling studies on the ion effects in RNA folding are based on the mean-field Poisson-Boltzmann approaches. These approaches do not consider correlations, fluctuations or finite size of the ions. However, a variety of experiments have pointed to the potential importance of these three effects for multivalent ions such as magnesium. Because magnesium ions are essential for RNA tertiary structure folding, the inability to treat the correlation/fluctuation and ion size effects has greatly limited the understanding, prediction, and design RNAs in various applications. This project will address this deficiency in theory by developing a new model for understanding the to role of divalent ions on the RNA structure and function.Broader impacts: Quantitative predictions for the ion effects in RNA folding will impact a broad range of RNA-related research, including quantification of the stabilizing forces in RNA, prediction of RNA stability and folding cooperativity, quantitative understanding of the mechanisms of ribozymes, riboswitches and microRNAs, and rational design of therapeutic RNA aptamers. The project will provide unique educational and training opportunities for graduate and post doctoral student coming from traditional physical science backgrounds and allow them to move into the field of biophysics.