MeCP2 is a protein highly expressed in the brain that participates in the genetic expression and RNA splicing regulation. MeCP2 binds preferably to methylated DNA and other nuclear corepressors to alter chromatin. MECP2 gene mutations can cause rett syndrome (RTT), a severe neurological disorder that affects around one in ten thousand girls. In this paper, Molecular Dynamics (MD) simulations were performed to scrutinize how the MeCP2 P152R mutation influences the protein binding to DNA. Also, the Umbrella Sampling technique was used to obtain the potential mean forces (PMFs) of both wild-type and mutated MeCP2 Methyl-CpG-binding domain (MBD) binding to both non-methylated and methylated DNA. P152R is a common missense mutation in MBD associated with RTT; however, there are no studies that explain how it causes protein dysfunction. The results from this study hypothesize that P152R mutation leads to MBD binding more strongly to DNA, while selectively decreasing binding affinity to methylated DNA. These provide an explanation for previous not conclusive experimental results regarding the mechanism of how this mutation affects the binding of the protein to DNA, and subsequently its effects on RTT. Furthermore, the results of this research-in-progress can be used as the basis for further investigations into the molecular basis of RTT and to potentially reveal a target for therapy in the future.

中文翻译：

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MeCP2中的P152R突变会导致DNA结合选择性的丧失。

MeCP2是一种在大脑中高表达的蛋白质，参与基因表达和RNA剪接调控。MeCP2优选与甲基化的DNA和其他核共抑制因子结合以改变染色质。MECP2基因突变可引起rett综合征（RTT），这是一种严重的神经系统疾病，影响约一万名女孩。在本文中，进行了分子动力学（MD）模拟，以详细研究MeCP2 P152R突变如何影响蛋白质与DNA的结合。同样，使用伞采样技术获得与未甲基化和甲基化DNA结合的野生型和突变的MeCP2甲基-CpG结合域（MBD）的潜在平均力（PMF）。P152R是与RTT相关的MBD中常见的错义突变；但是，没有研究可以解释它如何导致蛋白质功能障碍。这项研究的结果假设，P152R突变会导致MBD与DNA的结合更牢固，同时选择性降低与甲基化DNA的结合亲和力。这些为先前关于该突变如何影响蛋白质与DNA结合以及随后对RTT的影响机理的非决定性实验结果提供了解释。此外，该正在进行的研究的结果可以用作进一步研究RTT分子基础的基础，并有可能在将来揭示治疗靶标。这些为先前关于该突变如何影响蛋白质与DNA结合以及随后对RTT的影响机理的非决定性实验结果提供了解释。此外，该正在进行的研究的结果可以用作进一步研究RTT分子基础的基础，并有可能在将来揭示治疗靶标。这些为先前关于该突变如何影响蛋白质与DNA结合以及随后对RTT的影响机理的非决定性实验结果提供了解释。此外，该正在进行的研究的结果可以用作进一步研究RTT分子基础的基础，并有可能在将来揭示治疗靶标。