Theoretical and Computational Modeling of Target-Site Search Kinetics In Vitro and In Vivo
Theoretical and Computational Modeling of Target-Site Search Kinetics In Vitro and In Vivo
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DOI：
10.1016/j.bpj.2011.06.066
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发表时间：
2011-08-17
影响因子：
3.4
通讯作者：
Spakowitz, Andrew J.
中科院分区：
文献类型：
--
作者：
Koslover, Elena F.;Diaz de la Rosa, Mario A.;Spakowitz, Andrew J.
获取遗传编码数据取决于DNA结合蛋白在基因组中搜索特定靶位点的动力学。这个搜索过程被认为是通过促进扩散发生的，三维扩散和一维滑动的结合。尽管易化扩散能够显著加速体外搜索，但这种机制在体内的重要性仍不清楚。我们使用数值模拟和分析理论来模拟DNA结合蛋白在各种条件下的目标搜索动力学。我们的模型再现了大量体外实验中搜索速率增强的实验测量，以及体内测量的转录因子的目标搜索时间。我们发现，促进扩散可以加速搜索过程，只有在有限的参数范围内，只有在稀释的DNA条件下。我们解决的作用，DNA的配置和限制，表明促进扩散并没有加快搜索卷曲与直的DNA。此外，我们表明，在体内条件下，搜索过程变得有效扩散，是独立的DNA配置。我们相信我们的结果为促进扩散在细胞内DNA靶向动力学中的作用提供了新的视角。
Access to genetically encoded data depends on the dynamics of DNA-binding proteins searching for specific target sites in the genome. This search process is thought to occur by facilitated diffusion a combination of three-dimensional diffusion and one-dimensional sliding. Although facilitated diffusion is capable of significantly speeding up the search in vitro, the importance of this mechanism in vivo remains unclear. We use numeric simulations and analytical theory to model the target-search dynamics of DNA-binding proteins under a wide range of conditions. Our models reproduce experimental measurements of search-rate enhancement within bulk in vitro experiments, as well as the target search time for transcription factors measured in vivo. We find that facilitated diffusion can accelerate the search process only for a limited range of parameters and only under dilute DNA conditions. We address the role of DNA configuration and confinement, demonstrating that facilitated diffusion does not speed up the search on coiled versus straight DNA. Furthermore, we show that, under in vivo conditions, the search process becomes effectively diffusive and is independent of DNA configuration. We believe our results cast in a new light the role of facilitated diffusion in DNA targeting kinetics within the cell.