通过结合分子动力学和多重对接方法研究乙胆酶的酶结合特异性
Jeremy Kua1, Yingkai Zhang, J Andrew McCammon
1Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0365, USA. jkua@mccammon.ucsd.edu
Journal of the American Chemical Society
|July 11, 2002
概括
乙胆酶 (AChE) 使用其和阳离子子子位点专门结合乙胆 (ACh). 在AChE中诱导适合通过稳定催化三合体和收紧子站点来增强结合.
科学领域:
- 生物化学 生物化学
- 计算化学计算化学
- 酶学 是一种酶学.
背景情况:
- 乙胆酶 (AChE) 是神经传递中的关键酶,负责化乙胆 (ACh).
- 了解ACHE的基质结合特异性对于设计有效的抑制剂和理解其生理作用至关重要.
研究的目的:
- 研究乙胆酶 (AChE) 与其天然基质乙胆 (ACh) 和相关分子的结合特异性.
- 阐明在实现基质结合特异性方面的和子子位点的作用.
- 探索诱导适合对基质结合和催化效率的影响.
主要方法:
- 采用了组合的分子动力学模拟和多重连接体对接方法.
- 计算了对接能量,并将它们与实验动力和结合亲和力数据相关联.
- 在基质结合时分析了ACHE活性部位内的结构变化和相互作用.
主要成果:
- 接能量与实验k ((cat) /K ((M)) 值和TMTFA 抑制剂的结合亲和力有很好的相关性.
- 和阳离子子子位共同决定基质结合特异性.
- ACh结合诱导了AChE的构造变化,稳定了催化三合体并增强了子站点相互作用,产生0.7 kcal/mol的对接能量增益.
- 基质尾组大小和正电荷对于与阳离子子站点的结合至关重要,电荷去除使结合减弱1kcal/mol.
结论:
- AChE通过其和离子子子位点的协同作用来实现基质特异性.
- 诱导适应在优化 ACh 结合和催化装置方面发挥着重要作用.
- 基质的结构特征,特别是尾组的电荷和大小,对于有效地与阳离子子基层结合至关重要.
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