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通过差异性HDX-MS和分子动力学模拟对KRas G12D抑制剂的相互作用进行表征

Evgeniy V Petrotchenko¹, Brandon Novy², Edith Nagy³

¹Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

Computational and structural biotechnology journal

|August 21, 2025

概括

小分子抑制剂稳定KRas G12D蛋白质结构,特别是在开关II口袋中,根据质谱 (MS) 和分子动力学 (MD) 模拟显示的-交换 (HDX).

科学领域:

生物化学
结构生物学
计算化学

背景情况:

蛋白质结构和动力学对于生物功能至关重要.
了解蛋白质与配体的相互作用是药物发现的关键.
KRas G12D是一个重要的瘤蛋白点.

研究的目的:

描述小分子抑制剂与KRas G12D的相互作用.
使用HDX-MS和MD模拟来研究抑制剂结合时的结构变化.
开发与实验HDX-MS数据和模拟结果相关的指标.

主要方法:

使用质谱测量 (HDX-MS) 进行完整蛋白和自下而上的交换.
自由和与抑制剂结合的KRas G12D的分子动态 (MD) 模拟.
分析键网络和二次结构变化.

主要成果:

在HDX-MS检测到在Switch-II口袋中的抑制剂结合时显著的保护.
MD模拟显示了Switch-II区域中改变的键网络.
提出了半经验性指标来关联HDX-MS和MD的发现.

结论:

结合HDX-MS和MD的方法为KRas G12D的结构变化提供了原子化的洞察力.
抑制剂结合稳定了KRas G12D蛋白质的结构.
这种方法可以帮助未来针对KRas G12D的药物设计工作.

关键词:

-交换质谱学分子动力学蛋白与药物结合

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Protein-protein Interfaces

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...