Cooperativity in Nucleic-Acid Protein Interactions

核酸-蛋白质相互作用中的协同性

基本信息

批准号：
1410172
负责人：
Ralf Bundschuh
金额：
$ 25.26万
依托单位：
Ohio State University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1410172&HistoricalAwards=false
关键词：
Cooperativity Nucleic Acid Protein Interactions

项目摘要

NON-TECHNICAL SUMMARYAny life form has to react to changes in its environment. In order to do so, it has to be able to process information. Information processing within individual cells boils down to interactions between different biomolecules that can come together in a multitude of different combinations. In order to process information, these interactions have to be cooperative, i.e., the interactions between one set of molecules have to depend on the presence or absence of other molecules. The PI's group will develop theoretical methods to model such cooperativity that will provide a better fundamental understanding of biological information processing and possibly the ability to engineer future biological information processing circuits. The research will be focused on two of the most important types of biomolecules, nucleic acids and proteins, and will have two different components. The first component will address the question of how natural structural properties of nucleic acids can generate cooperativity and how this new mechanism is used by living organisms. The second component will be of a more technological nature and will aim at improving the utilization of protein nucleic acid interactions to measure DNA methylation, a feature of cells that is known to be affected in many diseases. This project will contribute to the training of a new generation of researchers equipped with mathematical and biological skills that are important for the future progress in the life sciences. This will be achieved through students' education in Biophysics Graduate Program and participation in Biophysics Seminar series at the Ohio State University. TECHNICAL SUMMARYThis project will develop quantitative models to describe cooperativity in interactions between proteins and nucleic acids. Such interactions are at the foundation of biological information processing as well as of biotechnological applications. Accurate theoretical models make interpretation of today's quantitative experiments possible and allow a fundamental understanding of biological mechanisms and extraction of "hidden" parameters from measurements. Within this context, the project consists of two parts. The first part will address effect of RNA secondary structure on cooperativity of proteins binding and elucidate mechanism of how natural messenger RNAs implements logic operations among different protein "inputs" in post-transcriptional regulation. The second part consists of the development of a detailed model of the interactions between several MBD2 methyl-binding domains and (methylated) DNA molecules. These MBD2 domains are used in experiments for determining DNA methylation status in a genome-wide manner and it is anticipated that the model to be developed will improve accuracy of these DNA methylation measurements. Such genome-wide measurements of DNA methylation are of interest since DNA methylation is known to be affected in many diseases.

非技术摘要生命形式必须对其环境变化做出反应。为此，它必须能够处理信息。单个细胞内的信息处理归结为可以在多种不同组合中融合在一起的不同生物分子之间的相互作用。为了处理信息，这些相互作用必须是合作的，即，一组分子之间的相互作用必须取决于其他分子的存在或不存在。 PI的小组将开发理论方法来建模这种合作性，从而为生物信息处理提供更好的基本理解，并可能具有设计未来生物信息处理电路的能力。该研究将集中在两种最重要的生物分子，核酸和蛋白质，并具有两个不同的成分。第一个组成部分将解决核酸的自然结构特性如何产生合作的问题，以及活生物体如何使用这种新机制。第二个成分将具有更高的技术性质，旨在改善蛋白质核酸相互作用以测量DNA甲基化的利用，DNA甲基化是细胞的特征，该特征已知在许多疾病中受到影响。该项目将有助于培训新一代的研究人员，该研究人员配备了数学和生物学技能，这对于生命科学的未来进步很重要。这将通过学生在生物物理学研究生课程方面的教育以及俄亥俄州立大学的生物物理研讨会系列的参与来实现。技术摘要项目将开发定量模型，以描述蛋白质与核酸之间相互作用的合作性。这种相互作用是生物信息处理以及生物技术应用的基础。准确的理论模型可以解释当今的定量实验，并允许对生物学机制和从测量结果中提取“隐藏”参数的基本理解。在这种情况下，项目由两个部分组成。第一部分将解决RNA二级结构对蛋白质结合的合作的影响，并阐明自然信使RNA如何在转录后调节中实现不同蛋白“输入”之间的逻辑操作的机制。第二部分包括开发几个MBD2甲基结合结构域和（甲基化的）DNA分子之间相互作用的详细模型。这些MBD2结构域用于实验中，用于以全基因组的方式确定DNA甲基化状态，并且预计开发该模型将提高这些DNA甲基化测量值的准确性。由于已知在许多疾病中受到DNA甲基化的影响，因此对DNA甲基化的这种全基因组测量值是有意义的。