在二酸减少酶中对结合基质pKa的进化影响
Anil R Mhashal1, Yaron Pshetitsky1, Christopher M Cheatum2
1Department of Chemistry , Bar-Ilan University , Ramat-Gan 5290002 , Israel.
Journal of the American Chemical Society
|November 7, 2018
概括
一种叫做二酸减少酶 (DHFR) 的酶进化了以更有效地结合基质. 这项研究表明,酶的基本性增加与活性部位水的减少有关,这表明了进化适应.
科学领域:
- 生物化学
- 酵素学
- 分子进化
背景情况:
- 叶酸减少酶 (DHFR) 在叶酸代谢中起着至关重要的作用.
- 了解DHFR的异形演变,可以了解酶的适应.
- 基质pKa调节是酶催化效率的关键.
研究的目的:
- 研究DHFR活性位结构对基质pKa的影响.
- 探索DHFR异型的进化趋势.
- 要将活性部位的水分与基质的度相关联.
主要方法:
- 使用混合量子力学/分子力学 (QM/MM) 自由能量扰动方法.
- 计算了N5位的7,8-二叶酸的pKa.
- 分析了各种DHFR异型的结构差异和水分子动力学.
主要成果:
- 观察到N5基性从原始到进化的DHFR异型逐渐增加.
- 发现活性部位水分减少与N5 pKa增加之间存在相关性.
- 确定了M20循环在调节活性部位的疏水性和灵活性方面的作用.
结论:
- 活性部位的水分水平直接影响结合的7,8-二酸盐的pKa.
- 在DHFR的进化过程中,活动部位的水分被排除,从而增强了基质的结合.
- M20环是调节活性部位水分和酶进化的关键结构元素.
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