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Updated: Jun 25, 2025

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治疗性核酸的结构动态与酸骨干修饰的酸骨干修饰

Antonio Carlesso¹, Johanna Hörberg², Giuseppe Deganutti³

¹Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Box 431, SE-405 30 Gothenburg, Sweden.

NAR genomics and bioinformatics

|May 27, 2024

概括

化学修饰的反感性寡核酸 (ASO) 是有前途的治疗药物. 新的分子动力学模拟揭示了酸骨干的修改如何影响ASO结构和目标结合.

科学领域:

生物化学生化学
计算生物学计算生物学
药理学药理学是指药理学的学科.

背景情况:

反感性寡核酸 (ASO) 是工程核酸,对遗传疾病具有治疗潜力.
化学修饰,如酸 (PS) 骨架,增强ASO的稳定性和结合亲和力.
精确的分子动力学 (MD) 模拟需要对改性核酸进行可靠的力场参数.

研究的目的:

开发和验证力场参数,以模拟具有酸 (PS) 骨干修改的ASO.
研究PS修改对DNA,RNA和DNA/RNA杂交双重体的结构动态的影响.
了解PS修改如何影响ASO目标识别和蛋白质相互作用.

主要方法:

开发PS修饰核酸的新型力场参数.
广泛的全原子分子动力学 (MD) 模拟B-DNA,RNA和DNA/RNA混合复合体与单个PS替代.
模拟结果与实验中获得的结构数据的验证.

主要成果:

单个PS替代对有序DNA/RNA双重结构的影响最小.
在单链RNA和B-DNA中观察到酸化的实质性影响,与实验数据一致.
PS的修改诱导了NA中高和低扭转状态之间的转移,可能影响目标结合和蛋白质相互作用.
在PS修饰的ssRNA中,符合性采样发生了显著的变化,这表明对双重组的形成有序依赖的影响.

结论:

开发的力场参数使PS修改的ASO能够准确地进行MD模拟.
酸化对某些核酸结构,特别是单链形式的构造动态有显著的影响.
这些发现为治疗ASO的结构功能关系提供了关键的见解,有助于药物设计和开发.

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