通过自由能量扰动通过人类启动因子eIF4E对mRNA盖结合的热力学分析
Cristiano R W Guimarães1, David J Kopecky, Jeff Mihalic
1Department of Molecular Structure, Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA.
Journal of the American Chemical Society
|November 21, 2009
概括
欧核细胞mRNA上的7甲基瓜诺辛盖增强了翻译启动因子eIF4E的结合. 这种改善的亲和力是由于有利的范德瓦尔斯相互作用和减少甲基组的溶解惩罚.
科学领域:
- 分子生物学分子生物学
- 生物物理学的生物物理.
- 计算化学计算化学
背景情况:
- 细胞mRNA的翻译启动依赖于7-甲基瓜诺辛盖 (m7GpppX).
- 细胞翻译启动因子4E (eIF4E) 与mRNA帽结构直接相互作用.
- 之前的研究表明m7GTP比非甲基化GTP更有利地与eIF4E结合.
研究的目的:
- 以热力学分析eIF4E与各种帽子类型的结合.
- 阐明7-甲基组在eIF4E/m7GpppX cap相互作用中的特定作用.
主要方法:
- 蒙特卡洛 (MC) 的模拟.
- 自由能量扰动 (FEP) 的计算.
- 对于帽子类型 (m7GTP,GTP,质子化GTP,m7DTP,DTP) 的结合自由能量的热力学分析.
主要成果:
- 与GTP相比,GTP上的N(7) 甲基组贡献了与GTP相比约束自由能量增加的一半.
- 观察到与Trp166的有利范德瓦尔斯相互作用,并减少了N(7) 原子的溶解惩罚.
- 剩余的亲和力增长与瓜宁部分的正电荷有关,促进了与Trp56和Trp102.2的阴离子-pi相互作用.
结论:
- 7甲基组通过固体和电子效应显著增强了eIF4E的结合亲和力.
- 范德瓦尔斯相互作用和改变的溶解都有助于甲基组的效应.
- 静电相互作用,特别是阴离子-π 相互作用,进一步稳定了该复合体.
相关概念视频
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