Hu Longhua, Grosberg Alexander Y, Bruinsma Robijn
Department of Physics, University of Minnesota, Minneapolis, Minnesota, USA.
Biophys J. 2008 Aug;95(3):1151-6. doi: 10.1529/biophysj.108.129825. Epub 2008 May 2.
Transcription factor (TF) proteins rapidly locate unique target sites on long genomic DNA molecules--and bind to them--during gene regulation. The search mechanism is known to involve a combination of three-dimensional diffusion through the bulk of the cell and one-dimensional sliding diffusion along the DNA. It is believed that the surprisingly high target binding rates of TF proteins relies on conformational fluctuations of the protein between a mobile state that is insensitive to the DNA sequence and an immobile state that is sequence-sensitive. Since TFs are not able to consume free energy during their search to obtain DNA sequence information, the Second Law of Thermodynamics must impose a strict limit on the efficiency of passive search mechanisms. In this article, we use a simple model for the protein conformational fluctuations to obtain the shortest binding time consistent with thermodynamics. The binding time is minimized if the spectrum of conformational fluctuations that take place during the search is impedance-matched to the large-scale conformational change that takes place at the target site. For parameter values appropriate for bacterial TF, this minimum binding time is within an order-of-magnitude of a limiting binding time corresponding to an idealized protein with instant target recognition. Numerical estimates suggest that typical bacteria operate in this regime of optimized conformational fluctuations.
转录因子(TF)蛋白在基因调控过程中能迅速在长基因组DNA分子上定位独特的靶位点并与之结合。已知搜索机制涉及在细胞主体内的三维扩散和沿DNA的一维滑动扩散。据信,TF蛋白惊人的高靶标结合率依赖于蛋白质在对DNA序列不敏感的移动状态和对序列敏感的固定状态之间的构象波动。由于转录因子在搜索过程中无法消耗自由能来获取DNA序列信息,热力学第二定律必然对被动搜索机制的效率施加严格限制。在本文中,我们使用一个简单的蛋白质构象波动模型来获得与热力学一致的最短结合时间。如果搜索过程中发生的构象波动谱与靶位点发生的大规模构象变化阻抗匹配,则结合时间将最小化。对于适合细菌TF的参数值,这个最小结合时间与具有即时靶标识别能力的理想化蛋白质的极限结合时间在一个数量级内。数值估计表明,典型细菌在这种优化构象波动的状态下运作。