Cooperativity in Nucleic-Acid Protein Interactions

任何生命形式都必须对环境的变化做出反应。 为了做到这一点，它必须能够处理信息。 单个细胞内的信息处理归结为不同生物分子之间的相互作用，这些生物分子可以以多种不同的组合方式聚集在一起。 为了处理信息，这些交互必须是合作的，即，一组分子之间的相互作用必须取决于其它分子的存在或不存在。 PI的小组将开发理论方法来模拟这种协同性，这将提供对生物信息处理的更好的基本理解，并可能具有设计未来生物信息处理电路的能力。 这项研究将集中在两种最重要的生物分子，核酸和蛋白质，并将有两个不同的组成部分。 第一部分将解决核酸的自然结构特性如何产生协同性以及生物体如何使用这种新机制的问题。 第二个组成部分将更具技术性，旨在改善蛋白质核酸相互作用的利用，以测量DNA甲基化，这是已知在许多疾病中受到影响的细胞特征。 该项目将有助于培养新一代的研究人员，他们具备对生命科学未来进步至关重要的数学和生物技能。 这将通过学生在生物物理研究生课程的教育和生物物理研讨会系列在俄亥俄州州立大学的参与来实现。本项目将开发定量模型来描述蛋白质和核酸之间相互作用的协同性。 这种相互作用是生物信息处理和生物技术应用的基础。 精确的理论模型使得对当今定量实验的解释成为可能，并允许对生物机制的基本理解和从测量中提取“隐藏”参数。 在这方面，该项目由两部分组成。 第一部分主要探讨RNA二级结构对蛋白质结合协同性的影响，阐明天然信使RNA在转录后调控中如何在不同蛋白质“输入”之间进行逻辑运算的机制。 第二部分包括几个MBD2甲基结合结构域和（甲基化）DNA分子之间的相互作用的详细模型的发展。 这些MBD2结构域用于以全基因组方式确定DNA甲基化状态的实验中，并且预期待开发的模型将提高这些DNA甲基化测量的准确性。 DNA甲基化的这种全基因组测量是令人感兴趣的，因为已知DNA甲基化在许多疾病中受到影响。

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.