Dynamics of DNA conformations and quantification of random search mechanisms in gene regulation

DNA 构象动力学和基因调控中随机搜索机制的量化

• 批准号: 327260-2006
• 负责人: Metzler, Ralf
• 金额: $ 3.23万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2006
• 资助国家: 加拿大
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=336577
• 关键词: Dynamics; DNA; conformations; quantification; random

Essentially all the biological functions of DNA rely on site-specific DNA-binding proteins finding their targets, and therefore searching through thousands of bases of non-target DNA in a very efficient manner. It is the goal of this project to study in detail the mechanisms of this search process as an interplay of protein-DNA interactions. For instance, we want to quantify the effect that proteins can hold on to two separate sites of DNA at places where DNA, like spaghetti on a plate, winds back on itself and forms little loops. By a short jump in space, that is, the protein covers the distance of the whole loop on the DNA. DNA therefore helps the protein in its target search. The resulting motion is called a Levy flight, a mechanism, that has been recognized as an efficient search strategy for various biological species, from gazing bacteria to jackals, spider monkeys, and albatross birds. At the same time, the project is aimed at extending our current models of DNA, that treat it the same way as other polymers such as polyethylene, despite DNA's complex interaction with its environment, in particular, the fact that binding proteins significantly change the properties of DNA. One of the unresolved questions we want to address is how an extremely small number of proteins in a cell can maintain a high fidelity and efficiency in the regulation of cellular processes, or in response to external stimuli. To this end, we will combine and expand knowledge from both physics and biochemistry in computer simulations and abstracted analytical models. Finally, we want to explore possibilities to design "in silico" genetic circuits, to study in a more defined manner genetic regulation, but also to develop new sensors that, on the nanometre scale, can combine and partially process several incoming signals, like the simultaneous presence of certain proteins. The project will involve collaboration with the Williams and Krichevsky single molecule labs in Boston and Be'er Sheva, as well as with the lab of Mads Kaern, who holds a Canada Research Chair in Systems Biology at the University of Ottawa. The results of this research are expected to impact our understanding of DNA and gene regulation, and open up new directions in biotechnology.

从本质上讲，DNA的所有生物学功能都依赖于特定位点的DNA结合蛋白找到它们的靶标，因此以一种非常有效的方式搜索非靶标DNA的数千个碱基。这个项目的目标是详细研究这个搜索过程的机制，作为蛋白质- dna相互作用的相互作用。例如，我们想要量化蛋白质在DNA的两个独立位点上的作用，DNA就像盘子上的意大利面一样，自我缠绕并形成小圈。通过在空间上的短暂跳跃，也就是说，蛋白质覆盖了DNA上整个环的距离。因此，DNA帮助蛋白质寻找目标。由此产生的运动被称为利维飞行，这是一种被认为是各种生物物种的有效搜索策略，从凝视的细菌到胡狼，蜘蛛猴和信天翁鸟。与此同时，该项目旨在扩展我们目前的DNA模型，将其与其他聚合物（如聚乙烯）一样对待，尽管DNA与环境存在复杂的相互作用，特别是结合蛋白会显著改变DNA的性质。我们想要解决的一个尚未解决的问题是，细胞中极少量的蛋白质如何在调节细胞过程或响应外部刺激时保持高保真度和效率。为此，我们将在计算机模拟和抽象分析模型中结合和扩展物理学和生物化学的知识。最后，我们想探索设计“硅”遗传电路的可能性，以更明确的方式研究遗传调控，同时也开发新的传感器，在纳米尺度上，可以组合和部分处理几个输入信号，比如同时存在某些蛋白质。该项目将涉及与波士顿的威廉姆斯和克里切夫斯基单分子实验室以及贝尔舍瓦，以及渥太华大学系统生物学加拿大研究主席Mads Kaern的实验室的合作。这项研究的结果有望影响我们对DNA和基因调控的理解，并为生物技术开辟新的方向。