Molecular Dissection of Cardiovascular Disease: From Genes to Models to Function

II型拓扑异构酶是所有生物体共有的必需酶。它们的细胞功能包括 保持染色体紧凑的水平，并确保细胞分裂时适当的分离。在……里面 此外，它们还经常被用作抗菌剂和抗癌药物的靶标。了解 拓扑异构酶II(Topo II)简化其DMA底物的拓扑复杂性的过程 关键的重要性。通过在分子水平上很好地理解的剪切粘贴机制，Topo II 能够通过一个DMA段传递另一个段。Topo II如何识别这两个DMA数据段仍是个问题 不清楚。众所周知，Topo II可以将DMA解结和解压到低于随机预期的水平 绞股式通道。这些和其他实验观察表明，手性驱动的非随机 TOPO II的作用机制。大量的实验和理论研究已经解决了这些问题 问题。然而，对TOPO II的机制仍然缺乏一个清晰的图景。我们的长期目标是 通过拓扑图II为拓扑化简的机理找到了一个准确的模型。 DNA解结的过程。我们的目标是验证Topo II是否有能力解开 最小可能数量的链-通道，或者手性偏差是否与其他局部 信息足以达到实验观察到的解结水平。我们提出了一个 跨学科方法，涉及基于数学纽带的复杂理论框架 理论和蒙特卡罗计算机模拟，并进行了实验验证。这台电脑 实现基于一种新的思想，与其他方法相比，它将大大减少计算时间 解开的计算模型。 与公共卫生相关：我们的方法将使我们能够有效地模拟野生型TOPO II 任何DNA结的分布。除了具有理论意义外，这样的模型还与公众相关 健康。解结试验用于抗癌药物的设计，以确定新的Topo II抑制剂。 我们的工作将应用于量化给定生物体的TOPO II的解结能力 并且没有抑制剂的存在，从而建立了对抑制剂的精确测量 有效性。

Type II topoisomerases are essential enzymes common to all organisms. Their cellular functions include maintaining the levels of chromosome compaction and ensuring proper segregation at cell division. In addition they are often used as targets for antimicrobial agents and anticancer drugs. Understanding the process by which topoisomerase II (topo II) simplifies the topological complexity of its DMA substrate is of key importance. By a cut-and-paste mechanism, which is well understood at the molecular level, topo II is able to pass a DMA segment through another. How topo II recognizes the two DMA segments is still unclear. Topo II is known to unknot and decatenate DMA to levels below those expected by random strand-passage. These and other experimental observations suggest a chirality-driven non-random mechanism of topo II action. Numerous experimental and theoretical studies have addressed these questions. However a clear picture of the mechanism of topo II is still lacking. Our long-term goal is to find an accurate model for the mechanism of topology simplification by topo II. We here focus on the process of DNA unknotting. Our objective is to verify whether topo II has the ability to unknot DMA in the smallest possible number of strand-passages, or whether a chirality bias combined with other local information are sufficient to reach the experimentally observed unknotting levels. We propose an interdisciplinary approach involving a sophisticated theoretical framework based on mathematical knot theory and Monte Carlo computer simulations, and followed by experimental validation. The computer implementation is based on a novel idea which will greatly reduce computation time as compared to other computational models of unknotting. Relevance to Public Health: Our method will give us the ability to efficiently simulate wild-type topo II on any distribution of DNA knots. Besides being of theoretical interest, such modeling is relevant to public health. Unknotting assays are used in the design of anti-cancer drugs to identify new topo II inhibitors. Our work will be applied to quantifying the unknotting capabilities of the topo II of a given organism with and without the presence of an inhibitor, thus establishing a precise measure of the inhibitor's effectiveness.