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解读BCL9三醇合的动态

Vikram Gaikwad¹, Asha Rani Choudhury¹, Rajarshi Chakrabarti¹

¹Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.

Biophysical chemistry

|February 9, 2024

概括

醇结稳定了BCL9,减少了它们的结构灵活性. 这种结构稳定增强了螺旋性质,为开发用于癌症治疗的新型Wnt信号通路抑制剂铺平了道路.

科学领域:

计算化学和结构生物学
分子动力学模拟的模拟.
的设计和药物的发现.

背景情况:

Wnt信号通路在细胞过程中至关重要,其失调与瘤生长有关.
在这种途径中,BCL9蛋白作为协同激活剂,与β-catenin相互作用.
抑制β-catenin/BCL9相互作用是一项治疗挑战,模仿BCL9螺旋域的酸是一种有希望的策略.

研究的目的:

用分子动力学模拟来研究单双三醇接BCL9的构造性行为.
探索三醇基质如何影响BCL9的二次结构和构造空间.
通过使用复制品交换与溶性温度 (REST2) 模拟来验证这些发现.

主要方法:

分子动力学 (MD) 模拟是在实验合成的单双酸和双酸的BCL9上进行的.
复制品交换与溶液温度 (REST2) 模拟被用于评估高温反应.
主要组件分析 (PCA) 和t分布式静态邻居嵌入 (t-SNE) 用于数据分析.

主要成果:

三醇接显著减少了BCL9的构造空间.
合的螺旋性质随着 triazole 交叉链接器之间的分离越来越大而增加.
通过PCA和t-SNE分析的REST2模拟显示,在添加三醇主干剂后,明显的集群形成减少.

结论:

三醇接是一种有效的策略,可以稳定BCL9的螺旋结构.
这项研究提供了对主干二次结构的潜在相互作用的洞察.
这些发现支持进一步开发三醇结合的BCL9作为癌症治疗中β-catenin/BCL9相互作用的潜在抑制剂.

关键词:

主要组成部分分析 (PCA)复制品交换与溶液化 (REST2) 的复制品交换拼接的类.T分布式 - 随机邻居嵌入 (t-SNE)三醇交叉连接器的交叉连接器

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