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特定部位的DNA结合蛋白找到它们的靶标，因此以非常有效的方式在数千个非靶标DNA碱基中搜索。这个项目的目标是详细研究作为蛋白质-DNA相互作用的这一搜索过程的机制。例如，我们想要量化蛋白质在DNA的两个不同位置上的作用，在这些位置，DNA就像盘子里的意大利面一样，卷曲起来形成小环。通过在太空中的一次跳跃，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。由此产生的动议被称为利维飞行，这是一种被认为是对各种生物物种的有效搜索策略，从凝视细菌到狼、蜘蛛猴和信天翁。与此同时，该项目的目标是扩展我们目前的DNA模型，这些模型以与聚乙烯等其他聚合物相同的方式对待它，尽管DNA与其环境的相互作用复杂，特别是结合蛋白显著改变了DNA的性质。我们想要解决的一个悬而未决的问题是，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度的保真度和效率。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和生物化学的知识。最后，我们希望探索设计“电子”遗传电路的可能性，以更明确的方式研究基因调控，并开发新的传感器，这种传感器可以在纳米尺度上结合并部分处理几个传入信号，如某些蛋白质的同时存在。该项目将涉及与波士顿的Williams和Krichevsky单分子实验室和Be‘er Sheva的合作，以及与在渥太华大学担任加拿大系统生物学研究教席的Mads Kairn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.