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转录因子MycMax,Omomyc同位体和DNA上的MaxMax识别的能量和结构动态驱动因素
1Department of Physics and Astronomy, University of California, Irvine, California, USA.
Physical chemistry chemical physics : PCCP
|November 27, 2025
概括
基本的螺旋环-螺旋环-氨酸拉链 (bHLHLZ) 转录因子通过E-box图案将DNA结合在一起. 分子动力学模拟揭示了蛋白质-DNA相互作用和序列特异性,提供了针对癌症相关转录的见解.
科学领域:
- 分子生物学分子生物学
- 生物物理学的生物物理.
- 计算生物学 计算生物学
背景情况:
- 基本螺旋环-螺旋环-氨酸拉链 (bHLHLZ) 转录因子 (TF) 是基因表达的关键调节者.
- 这些TF,包括MycMax,MaxMax和Omomyc,与称为E盒 (5'-CACGTG-3') 的特定DNA序列结合.
- 了解TF-DNA相互作用的生物物理机制是解读基因调节和开发治疗策略的关键,特别是在癌症中.
研究的目的:
- 研究MycMax,MaxMax和Omomyc二元体与正规E盒和多ADNA序列的分子动力学和能量相互作用.
- 阐明特定氨基酸残留和DNA链关联在TF-DNA识别和结合特异性中的作用.
- 为了比较这些TFs在不同DNA序列上的结合稳定性和动态,并了解Myc驱动的转录在瘤发生过程中的含义.
主要方法:
- 使用微秒分子动力学 (MD) 模拟来建模TF-DNA相互作用.
- 用MMGBSA (分子力学与一般化天生的表面积) 计算进行了能量分析.
- 进行了结合 (HB) 和每残留物分解分析,以确定关键的相互作用点和作用力.
主要成果:
- 蛋白质-DNA范德瓦尔斯 (VDW) 相互作用和表面互补性是结合亲和力的主要因素.
- 保存的阿基尼因残留物在蛋白质-DNA接口中发挥着关键作用.
- 马克斯马克斯表现出强烈的依赖于E盒模式,在多ADNA上失去稳定性,而Omomyc与MycMax相比显示出增强的结合稳定性,这表明Myc在癌症中可能被封存.
结论:
- 模态bHLHLZ-TFs通过VDW力,表面互补性和特定残留相互作用的组合来识别DNA.
- 基因链关联偏差有助于TFs对特定序列的识别.
- 这些发现为TF-DNA结合提供了物理洞察力,并建议Omomyc作为抑制癌症Myc驱动转录的潜在治疗标.
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