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

基本上，DNA的所有生物学功能都依赖于位点特异性DNA结合蛋白找到它们的靶点，从而以非常有效的方式搜索非靶DNA的数千个碱基。该项目的目标是详细研究这种搜索过程作为蛋白质-DNA相互作用的相互作用的机制。例如，我们想要量化蛋白质可以固定在DNA的两个独立位点上的效果，在这些位点上，DNA就像盘子里的意大利面一样，会自行折回并形成小循环。通过空间上的一小段跳跃，也就是说，蛋白质覆盖了DNA上整个环的距离。因此，DNA有助于蛋白质寻找目标。由此产生的运动被称为Levy飞行，这是一种机制，已被公认为各种生物物种的有效搜索策略，从凝视细菌到豺狼，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）以相同的方式处理，尽管DNA与其环境的复杂相互作用，特别是结合蛋白质显着改变DNA的特性。我们想要解决的一个尚未解决的问题是，细胞中极少数的蛋白质如何能够在细胞过程的调节或对外部刺激的反应中保持高保真度和效率。为此，我们将联合收割机，并扩大知识，从物理和生物化学在计算机模拟和抽象的分析模型。最后，我们希望探索设计“计算机”遗传电路的可能性，以更明确的方式研究遗传调控，同时开发新的传感器，在纳米尺度上，可以联合收割机并部分处理几个输入信号，例如某些蛋白质的同时存在。该项目将涉及与波士顿和Be'er Sheva的威廉姆斯和Krichevsky单分子实验室以及Mads Kaern实验室的合作，Mads Kaern在渥太华大学担任加拿大系统生物学研究主席。这项研究的结果有望影响我们对DNA和基因调控的理解，并开辟生物技术的新方向。

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.