Mixed lineage leukemia protein (MLL1 protein) recognizes the CpG site via its CXXC domain and is frequently associated with leukemia. The specific recognition is abolished by C1188D mutation, which also prevents MLL‐related leukemia. In this paper, multiple molecular dynamic (MD) simulations were performed to investigate the mechanism of recognition and influences of C1188D mutation. Started from fully dissociated DNA and MLL1‐CXXC domain, remarkably, the center of mass (COM) of MLL1‐CXXC domain quickly concentrates on the vicinity of the CpG site in all 53 short MD simulations. Extended simulations of the wild type showed that the native complex formed in 500 ns among 4 of 53 simulations. In contrast, the C1188D mutant COM distributed broadly around the DNA and the native complex was not observed in any of the extended simulations. Simulations on the apo MLL1‐CXXC domain further suggest that the wild type protein remained predominantly in an open form that closely resembles its structure in the native complex whereas C1188D mutant formed predominantly compact structures in which the N‐ terminal bends to D1188. This conformational switch hinders the formation of encounter complex, thus abolishes the recognition. Our study also provides clues to the study mechanism of recognition, by the CXXC domain from proteins like DNA methyltransferase and ten‐eleven translocation enzymes.

中文翻译：

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C1188D突变通过诱导柔性N端的构象转换，消除了MLL1-CXXC域和CpG位点之间的特异性识别。

混合谱系白血病蛋白（MLL1蛋白）通过其CXXC结构域识别CpG位点，并经常与白血病相关。C1188D突变取消了特异性识别，该突变还预防了与MLL相关的白血病。在本文中，进行了多个分子动力学（MD）模拟，以研究C1188D突变的识别机理和影响。从完全分离的DNA和MLL1-CXXC结构域开始，值得注意的是，在所有53个简短的MD模拟中，MLL1-CXXC结构域的质心（COM）迅速集中在CpG位点附近。扩展的野生型模拟显示，在53个模拟中的4个模拟中，天然复合物在500 ns内形成。相反，C1188D突变体COM广泛分布在DNA周围，并且在任何扩展模拟中均未观察到天然复合物。对载脂蛋白MLL1-CXXC结构域的模拟进一步表明，野生型蛋白主要以开放形式保留，其形式与天然复合物中的结构极为相似，而C1188D突变体则主要形成紧凑的结构，其中N-末端弯曲至D1188。这种构象转换阻碍了相遇复合体的形成，从而取消了识别。我们的研究还提供了通过CXXC域识别DNA甲基转移酶和十一个11易位酶等蛋白质识别机制的线索。这种构象转换阻碍了相遇复合体的形成，从而取消了识别。我们的研究还提供了通过CXXC域识别DNA甲基转移酶和十一个11易位酶等蛋白质识别机制的线索。这种构象转换阻碍了遇到复合物的形成，从而取消了识别。我们的研究还提供了通过CXXC域识别DNA甲基转移酶和十一个11易位酶等蛋白质识别机制的线索。