Oncogenic protein Myc serves as a transcription factor to control cell metabolisms. Myc dimerizes via leucine zipper with its associated partner protein Max to form a heterodimer structure, which then binds target DNA sequences to regulate gene transcription. The regulation depends on Myc-Max binding to DNA and searching for target sequences via diffusional motions along DNA. Here, we conduct structure-based molecular dynamics (MD) simulations to investigate the diffusion dynamics of the Myc-Max heterodimer along DNA. We found that the heterodimer protein slides on the DNA in a rotation-uncoupled manner in coarse-grained simulations, as its two helical DNA binding basic regions (BRs) alternate between open and closed conformations via inchworm stepping motions. In such motions, the two BRs of the heterodimer step across the DNA strand one by one, with step sizes reaching about half of a DNA helical pitch length. Atomic MD simulations of the Myc-Max heterodimer in complex with DNA have also been conducted. Hydrogen bond interactions are revealed between the two BRs and two complementary DNA strands, respectively. In the non-specific DNA binding, the BR from Myc shows an onset of stepping on one association DNA strand and starts detaching from the other strand. Overall, our simulation studies suggest that the inchworm stepping motions of the Myc-Max heterodimer can be achieved during the protein diffusion along DNA.

致癌蛋白Myc作为控制细胞代谢的转录因子。Myc通过亮氨酸拉链及其相关的伴侣蛋白Max形成二聚体，形成异二聚体结构，然后与目标DNA序列结合以调节基因转录。该调节取决于Myc-Max与DNA的结合以及通过沿着DNA的扩散运动来搜索靶序列。在这里，我们进行基于结构的分子动力学（MD）模拟，以研究Myc-Max异二聚体沿DNA的扩散动力学。我们发现异二聚体蛋白在粗粒模拟中以旋转解耦的方式在DNA上滑动，因为它的两个螺旋DNA结合基本区域（BRs）通过足蠕虫的步进运动在打开和闭合构象之间交替。在这种运动中，异二聚体的两个BR一步一步跨过DNA链，步长达到DNA螺旋节距长度的一半。还进行了Myc-Max异二聚体与DNA复合的原子MD模拟。两个BR和两条互补DNA链之间分别揭示了氢键相互作用。在非特异性DNA结合中，来自Myc的BR表现出开始踩踏一个缔合DNA链并开始与另一链脱开的现象。总体而言，我们的模拟研究表明，Myc-Max异二聚体的蠕虫步进运动可以在蛋白质沿DN​​A扩散的过程中实现。在非特异性DNA结合中，来自Myc的BR表现出开始踩踏一条缔合DNA链并开始与另一条链脱开的现象。总体而言，我们的模拟研究表明，Myc-Max异二聚体的蠕虫步进运动可以在蛋白质沿DN​​A扩散的过程中实现。在非特异性DNA结合中，来自Myc的BR表现出开始踩踏一条缔合DNA链并开始与另一条链脱开的现象。总体而言，我们的模拟研究表明，Myc-Max异二聚体的蠕虫步进运动可以在蛋白质沿DN​​A扩散的过程中实现。