Xu Lishi, Ye Wei, Jiang Cheng, Yang Jingxu, Zhang Jinmai, Feng Yan, Luo Ray, Chen Hai-Feng
State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University , 800 Dongchuan Road, Shanghai, 200240, China.
J Phys Chem B. 2015 Feb 19;119(7):2844-56. doi: 10.1021/jp510940w. Epub 2015 Feb 9.
Lac repressor is a DNA-binding protein which inhibits the expression of a series of genes involved in lactose metabolism. Lac repressor can bind at a random DNA site via nonspecific interactions; then, it rapidly translocates through the double chain of DNA until it finds the specific binding site. Therefore, the site transform between these two modes is essential for the specific recognition between Lac repressor and DNA. Here, the recognition mechanism between Lac repressor and DNA was illustrated with molecular dynamics simulations and correlation network analyses. We have found that the correlation network of the specific system (2KEI) is more centralized and denser than that of the nonspecific system (1OSL). The significant difference in the networks between the nonspecific and specific systems is apparently due to the different binding modes. Then, different interaction modes were found where electrostatic and hydrogen bonding interactions in the nonspecific system are stronger than those in the specific system. Hydrophobic interactions were found only in specific complexes and mostly focused on the hinge helices. Furthermore, the hinge helix will induce the bending of DNA for the specific system. At the same time, a common specific sequence of DNA was revealed for three specific systems. Then, two design systems (positive and control) were used to evaluate the specific recognition between DNA and Lac repressor. These combined methods can be used to reveal the recognition mechanism between other transcription factors and DNA.
乳糖阻遏蛋白是一种DNA结合蛋白，它抑制一系列参与乳糖代谢的基因的表达。乳糖阻遏蛋白可以通过非特异性相互作用结合在随机的DNA位点上；然后，它沿着DNA双链快速移位，直到找到特异性结合位点。因此，这两种模式之间的位点转换对于乳糖阻遏蛋白与DNA之间的特异性识别至关重要。在此，通过分子动力学模拟和相关网络分析阐明了乳糖阻遏蛋白与DNA之间的识别机制。我们发现，特异性系统（2KEI）的相关网络比非特异性系统（1OSL）的更集中、更密集。非特异性系统和特异性系统之间网络的显著差异显然是由于不同的结合模式。然后，发现了不同的相互作用模式，其中非特异性系统中的静电和氢键相互作用比特异性系统中的更强。疏水相互作用仅在特异性复合物中发现，并且主要集中在铰链螺旋上。此外，铰链螺旋会导致特异性系统中DNA的弯曲。同时，揭示了三个特异性系统共有的DNA特异性序列。然后，使用两个设计系统（阳性和对照）来评估DNA与乳糖阻遏蛋白之间的特异性识别。这些组合方法可用于揭示其他转录因子与DNA之间的识别机制。
