QM/MM study of catalytic methyl transfer by the N5‐glutamine SAM‐dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme
QM/MM study of catalytic methyl transfer by the N5‐glutamine SAM‐dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme
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DOI：
10.1002/jcc.20793
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发表时间：
2008-02
影响因子：
3
通讯作者：
Ruibo Wu;Z. Cao
中科院分区：
文献类型：
--
作者：
Ruibo Wu;Z. Cao
结合密度泛函量子力学/分子力学（QM/MM）方法研究了N5-谷氨酰胺S-腺苷-L-蛋氨酸（SAM）依赖性甲基转移酶（HemK）和辅酶修饰的HemK（SAM被氮类似物取代）催化的甲基转移反应。计算表明，HemK的催化甲基转移是一个能量有利的过程，其活化能垒为15.7 kcal/mol，活化度为12.0 kcal/mol，而辅酶修饰的HemK由于20.6 kcal/mol的实质性势垒和产物中间体的不稳定性而不能催化甲基转移。实验结果支持了SAM辅酶的氮类似物应该是HemK催化甲基转移的实用抑制剂的实验建议。比较QM/MM计算表明，蛋白质环境，尤其是活性位点的Asn 197和Pro 198残基，在稳定过渡态和调节反应基团的定位方面起着关键作用.© 2007 Wiley Periodicals，Inc. J Comput Chem，2008年
The combined density functional quantum mechanical/molecular mechanical (QM/MM) approach has been used to investigate methyl‐transfer reactions catalyzed by the N5‐glutamine S‐adenosyl‐L‐methionine (SAM)‐dependent methyltransferase (HemK) and the coenzyme‐modified HemK with the replacement of SAM by a nitrogen analogue. Calculations reveal that the catalytic methyl transfer by HemK is an energy‐favored process with an activation barrier of 15.7 kcal/mol and an exothermicity of 12.0 kcal/mol, while the coenzyme‐modified HemK is unable to catalyze the methyl transfer because of a substantial barrier of 20.6 kcal/mol and instability of the product intermediate. The results lend support to the experimental proposal that the nitrogen analogue of the SAM coenzyme should be a practicable inhibitor for the catalytic methyl transfer by HemK. Comparative QM/MM calculations show that the protein environment, especially the residues Asn197 and Pro198 in the active site, plays a pivotal role in stabilizing the transition state and regulating the positioning of reactive groups. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008