Kochugaeva Maria P, Shvets Alexey A, Kolomeisky Anatoly B
Department of Chemistry, Rice University, Houston, Texas; Center for Theoretical Biological Physics, Rice University, Houston, Texas.
Department of Chemistry, Rice University, Houston, Texas; Center for Theoretical Biological Physics, Rice University, Houston, Texas.
Biophys J. 2017 Mar 14;112(5):859-867. doi: 10.1016/j.bpj.2017.01.018.
Genetic stability is a key factor in maintaining, survival, and reproduction of biological cells. It relies on many processes, but one of the most important is a homologous recombination, in which the repair of breaks in double-stranded DNA molecules is taking place with a help of several specific proteins. In bacteria, this task is accomplished by RecA proteins that are active as nucleoprotein filaments formed on single-stranded segments of DNA. A critical step in the homologous recombination is a search for a corresponding homologous region on DNA, which is called a homology search. Recent single-molecule experiments clarified some aspects of this process, but its molecular mechanisms remain not well understood. We developed a quantitative theoretical approach to analyze the homology search. It is based on a discrete-state stochastic model that takes into account the most relevant physical-chemical processes in the system. Using a method of first-passage processes, a full dynamic description of the homology search is presented. It is found that the search dynamics depends on the degree of extension of DNA molecules and on the size of RecA nucleoprotein filaments, in agreement with experimental single-molecule measurements of DNA pairing by RecA proteins. Our theoretical calculations, supported by extensive Monte Carlo computer simulations, provide a molecular description of the mechanisms of the homology search.
遗传稳定性是生物细胞维持、存活和繁殖的关键因素。它依赖于许多过程，但其中最重要的一个过程是同源重组，即双链DNA分子中的断裂在几种特定蛋白质的帮助下得以修复。在细菌中，这项任务由RecA蛋白完成，RecA蛋白作为在DNA单链片段上形成的核蛋白细丝而具有活性。同源重组中的一个关键步骤是在DNA上寻找相应的同源区域，这被称为同源性搜索。最近的单分子实验阐明了这一过程的一些方面，但其分子机制仍未得到很好的理解。我们开发了一种定量理论方法来分析同源性搜索。它基于一个离散状态随机模型，该模型考虑了系统中最相关的物理化学过程。使用首次通过过程的方法，给出了同源性搜索的完整动态描述。结果发现，搜索动力学取决于DNA分子的伸展程度和RecA核蛋白细丝的大小，这与RecA蛋白对DNA配对的实验单分子测量结果一致。我们的理论计算在广泛的蒙特卡罗计算机模拟的支持下，提供了同源性搜索机制的分子描述。
