Department of Chemistry, Rice University , Houston, Texas 77005, United States.
J Phys Chem B. 2013 Oct 24;117(42):12695-701. doi: 10.1021/jp311466f. Epub 2013 Jan 28.
Protein search for targets on DNA starts all major biological processes. Although significant experimental and theoretical efforts have been devoted to investigation of these phenomena, mechanisms of protein-DNA interactions during the search remain not fully understood. One of the most surprising observations is known as a speed-selectivity paradox. It suggests that experimentally observed fast findings of targets require smooth protein-DNA binding potentials, while the stability of the specific protein-DNA complex imposes a large energy gap which should significantly slow down the protein molecule. We developed a discrete-state stochastic approach that allowed us to investigate explicitly target search phenomena and to analyze the speed-selectivity paradox. A general dynamic phase diagram for different search regimes is constructed. The effect of the target position on search dynamics is investigated. Using experimentally observed parameters, it is found that slow protein diffusion on DNA does not lead to an increase in the search times. Thus, our theory resolves the speed-selectivity paradox by arguing that it does not exist. It is just an artifact of using approximate continuum theoretical models for analyzing protein search in the region of the parameter space beyond the range of validity of these models. In addition, the presented method, for the first time, provides an explanation for fast target search at the level of single protein molecules. Our theoretical predictions agree with all available experimental observations, and extensive Monte Carlo computer simulations are performed to support analytical calculations.
蛋白质在 DNA 上搜索目标启动了所有主要的生物过程。尽管已经投入了大量的实验和理论努力来研究这些现象，但蛋白质-DNA 相互作用的机制在搜索过程中仍然没有被完全理解。最令人惊讶的观察之一被称为速度选择性悖论。它表明，实验观察到的快速发现目标需要平滑的蛋白质-DNA 结合势，而特定蛋白质-DNA 复合物的稳定性则施加了一个大的能量间隙，这应该会显著减缓蛋白质分子的速度。我们开发了一种离散状态的随机方法，允许我们明确地研究目标搜索现象，并分析速度选择性悖论。构建了不同搜索机制的通用动态相图。研究了目标位置对搜索动力学的影响。使用实验观察到的参数，发现 DNA 上的蛋白质扩散缓慢不会导致搜索时间增加。因此，我们的理论通过争辩说它不存在来解决速度选择性悖论。这只是在超出这些模型的有效范围的参数空间区域中使用近似连续理论模型来分析蛋白质搜索时出现的一种假象。此外，所提出的方法首次在单个蛋白质分子水平上提供了对快速目标搜索的解释。我们的理论预测与所有现有的实验观察结果一致，并进行了广泛的蒙特卡罗计算机模拟以支持分析计算。
