通过dithiophosphate组的结合实现了增强的分散和极化相互作用,为RNA Aptamer-Thrombin复合物产生了显著的结合亲和度增加
Journal of the American Chemical Society
|February 23, 2019
概括
在RNA吸附体中用滴酸盐组替换酸盐组显著提高了蛋白质结合亲和力. 这种修饰在向血栓和VEGF的aptams中被发现,其结合力比原生RNA强1000倍.
科学领域:
- 生物化学
- 分子生物学
- 结构生物学
背景情况:
- 对于向蛋白质结合而言,RNA体具有至关重要的作用.
- 修改RNA基可以改变结合亲和力.
- 甲基酸盐 (PS2) 修改是增强蛋白质 - 配体相互作用的一种策略.
研究的目的:
- 调查二酸盐修饰RNA的结合性增强背后的机制.
- 量化极化,分散和溶解能量对结合亲和力的贡献.
- 了解蛋白质残留在二酸盐-RNA相互作用中的作用.
主要方法:
- 量子力学 (QM) 计算模型系统 (酸盐和丁酸盐衍生物).
- 量子力学/分子力学 (QM/MM) 对全胺蛋白复合体的计算.
- 分析原生和修饰的胺蛋白复合物的晶体结构.
主要成果:
- 酸与的相互作用明显强于酸的相互作用.
- QM/MM计算证实了更强的相互作用,并突出了基本残留物中的电场作用.
- 极化和分散能量对结合亲和度的增加起到关键作用,而溶解效应则不那么重要.
结论:
- 丁酸盐修饰的RNA体的增强结合亲和力主要是由于有利的极化和分散能量.
- 来自周围基本氨基酸残留物的电场 (例如,Phe-232附近) 在二酸盐部分的两极化中起着关键作用.
- 这种机制提供了一种总体策略,可以大大提高RNA受体对其蛋白质标的结合亲和力.
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