QM/MM metadynamics study of the direct decarboxylation mechanism for orotidine-5'-monophosphate decarboxylase using two different QM regions: acceleration too small to explain rate of enzyme catalysis.
QM/MM metadynamics study of the direct decarboxylation mechanism for orotidine-5'-monophosphate decarboxylase using two different QM regions: acceleration too small to explain rate of enzyme catalysis.
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DOI：
10.1021/jp074858n
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发表时间：
2007-11
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影响因子：
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通讯作者：
Courtney Stanton;I. W. Kuo;C. Mundy;T. Laino;Kendall N. Houk
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文献类型：
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作者：
Courtney Stanton;I. W. Kuo;C. Mundy;T. Laino;Kendall N. Houk
尽管经过数十年的研究，乳清酸苷-5 '-单磷酸脱羧酶（ODCase）催化乳清酸苷单磷酸脱羧的机制仍然没有得到解决。直接脱羧机制的计算研究已经进行了使用混合量子力学/分子力学（QM/MM）动力学模拟。该研究是与程序CP 2K，集成了经典动力学和从头算动力学的基础上Born-Oppenheimer方法。探索了两个不同的QM区域。乳清酸核苷-5 '-单磷酸（OMP）在溶液和酶中（使用较大的QM区域）直接脱羧的自由能垒用代谢动力学方法测定分别为40和33千卡/摩尔。因此，从溶液到酶的活化自由能（Δ Δ G ++）的计算变化为-7千卡/摩尔，远小于-23千卡/摩尔的实验变化（对于k（催化剂）/ k（uncat.）：Radzicka，A.;沃尔芬登河，Science 1995，267，90-92）。这些结果不支持已提出的酶的直接脱羧机制。然而，在QM/MM计算的上下文中，人们发现，QM区域的大小对计算的反应势垒有显着的影响。
Despite decades of study, the mechanism by which orotidine-5'-monophosphate decarboxylase (ODCase) catalyzes the decarboxylation of orotidine monophosphate remains unresolved. A computational investigation of the direct decarboxylation mechanism has been performed using mixed quantum mechanical/molecular mechanical (QM/MM) dynamics simulations. The study was performed with the program CP2K that integrates classical dynamics and ab initio dynamics based on the Born-Oppenheimer approach. Two different QM regions were explored. The free energy barriers for direct decarboxylation of orotidine-5'-monophosphate (OMP) in solution and in the enzyme (using the larger QM region) were determined with the metadynamics method to be 40 and 33 kcal/mol, respectively. The calculated change in activation free energy (DeltaDeltaG++) on going from solution to the enzyme is therefore -7 kcal/mol, far less than the experimental change of -23 kcal/ mol (for k(cat.)/k(uncat.): Radzicka, A.; Wolfenden, R., Science 1995, 267, 90-92). These results do not support the direct decarboxylation mechanism that has been proposed for the enzyme. However, in the context of QM/MM calculations, it was found that the size of the QM region has a dramatic effect on the calculated reaction barrier.