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Splicing, Folding, and Stretching Nucleic Acids

剪接、折叠和拉伸核酸

基本信息

批准号：
6666541
负责人：
DANIEL PAUL AALBERTS
金额：
$ 15.52万
依托单位：
WILLIAMS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6666541
关键词：
chemical models conformation model design /development molecular dynamics molecular site nucleic acid structure thermodynamics

项目摘要

DESCRIPTION (provided by applicant): Single-stranded nucleic acids fold into complex and compact shapes. Making accurate secondary structure predictions helps uncover function and cellular activity and is also of general interest as an analog of the protein folding problem. The following three proposals will expand the predictive power of physical chemical models of nucleic acid conformations. (1) Gene finding algorithms are currently statistics based. We, like cells, favor a thermodynamics-based approach to locating splice sites. Preliminary results show that snRNA binds better to real splice sequences than false. This work should lead to better gene recognition algorithms and a simple picture of splicing. (2) Revising current models and improving the functionality of secondary structure algorithms will help researchers interested in nucleic acid conformations. Algorithmic advances will likely be useful for other related problems such as anti-sense gene therapy and gene chip thermodynamic analysis. (a) Pseudoknots are excluded from popular dynamic-programming algorithms like MFOLD. Characterizing the "PseudoBase" database of known pseudoknots will help select an algorithm, which would then be implemented. (b) Current algorithms search for minimum energy conformations, but secondary structures may be trapped kinetically. A kinetic rule for folding based in polymer physics and implemented in a dynamic programming algorithm would allow the study of misfolding. (c) Unpaired regions are ignored in current models of folding, even though single-strand stacking enthalpies are nearly equal to those of duplex formation. By including these interactions, the accuracy of folding algorithms should improve. (d) Folding algorithms seek the lowest free energy state. Since the free energy differences between several conformations is small, the intrinsic uncertainty of the energy prediction may mean another state is lowest in energy. Characterizing the uncertainty will permit calculations of the likelihood of a correct prediction as a function of the number of nucleotides. (3) The development of our "Stacked or Freely Jointed Chain" (SFJC) model will provide a new context with which to study polymers whose conformational disorder arises from sharp kinks. Calculations are straightforward for this two-state model and preliminary results suggest they compare well with recent stretched DNA experiments. The SFJC is also handy for modeling single-stranded loop sections of RNA.

描述（由申请人提供）：单链核酸折叠成复杂和紧凑的形状。进行准确的二级结构预测有助于揭示功能和细胞活性，并且作为蛋白质折叠问题的类似物也受到普遍关注。以下三个建议将扩大核酸构象的物理化学模型的预测能力。 (1)基因发现算法目前是基于统计的。像细胞一样，我们也喜欢用基于生物学的方法来定位剪接位点。初步结果表明snRNA与真实的剪接序列的结合比假的更好。这项工作应该导致更好的基因识别算法和一个简单的图片拼接。 (2)修改现有的模型和改进二级结构算法的功能将有助于对核酸构象感兴趣的研究人员。该技术的发展对反义基因治疗、基因芯片热力学分析等相关问题的研究也有很大的帮助。 (a)伪结被排除在流行的动态编程算法（如MFOLD）之外。表征已知伪结的“伪Base”数据库将有助于选择算法，然后将实现该算法。 (b)目前的算法搜索最小能量构象，但二级结构可能被捕获动力学。基于聚合物物理学的折叠动力学规则和动态规划算法的实现将允许错误折叠的研究。 (c)在目前的折叠模型中，未配对的区域被忽略了，即使单链堆叠的折叠几乎等于双链体形成的折叠。通过包括这些相互作用，折叠算法的准确性应该得到提高。 (d)折叠算法寻找最低的自由能状态。由于几种构象之间的自由能差异很小，能量预测的内在不确定性可能意味着另一种状态的能量最低。表征不确定性将允许计算作为核苷酸数目的函数的正确预测的可能性。 (3)我们的“堆叠或自由连接链”（SFJC）模型的发展将提供一个新的背景下，研究聚合物的构象紊乱所产生的尖锐扭结。这种双态模型的计算很简单，初步结果表明它们与最近的拉伸DNA实验比较好。SFJC也便于建模RNA的单链环部分。