Quantifying the mechanism of phosphate monoester hydrolysis in aqueous solution by evaluating the relevant ab initio QM/MM free-energy surfaces.
Quantifying the mechanism of phosphate monoester hydrolysis in aqueous solution by evaluating the relevant ab initio QM/MM free-energy surfaces.
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DOI：
10.1021/jp4020146
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发表时间：
2013-10-24
期刊：
影响因子：
--
通讯作者：
Warshel A
中科院分区：
文献类型：
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作者：
Plotnikov NV;Prasad BR;Chakrabarty S;Chu ZT;Warshel A
了解磷酸盐水解的自由能表面的性质是理解生物学中相应的关键化学反应的先决条件。这里的挑战是转移到仔细的从头计算QM/MM （QM(ai)/MM）自由能计算，其中获得收敛结果是非常苛刻和计算昂贵的。这项工作描述了这样的计算，重点是磷酸单酯水解的自由能表面，特别注意质子转移（PT）步骤的一个水（1W）和两个水（2W）路径之间的比较。这个问题之前已经通过隐式溶剂模型的能量最小化和非系统QM/MM能量最小化以及非系统自由能映射来探索。然而，没有一项研究提供了得出具体结论所必需的可靠的2D （3D）表面。我们的研究以系统的方式生成了几个相关体系的二维（三维）自由能图，比较了QM(ai)/MM和QM(ai)/隐式溶剂表面的结果，并提供了相关能量学的高级描述。结果表明，二磷酸甲酯（MDP）三阴离子的1W水解路径比2W水解路径高6 ~ 9千卡/摩尔。这种差异在Mg2+离子的存在下变得稍大，因为Mg2+离子降低了接受质子的磷酸氧的共轭酸形式的pKa。有趣的是，BLYP方法（在一些研究中广泛使用）给出的1W和2W激活屏障之间的差异要小得多。无论如何，值得指出的是，PT的2W过渡状态并不比作为1W和2W PT路径起点的普通平台高多少。因此，基于2W PT机制模型计算的蛋白质催化效应预计不会与基于观察到的溶液中屏障校准的1W PT机制模型预测的催化效应不同（正如我们之前所有的EVB研究所做的那样）。
Understanding the nature of the free energy surfaces for phosphate hydrolysis is a prerequisite for understanding the corresponding key chemical reactions in biology. Here the challenge has been to move to careful ab initio QM/MM (QM(ai)/MM) free energy calculations, where obtaining converging results is very demanding and computationally expensive. This work describes such calculations, focusing on the free energy surface for the hydrolysis of phosphate monoesters, paying a special attention to the comparison between the one water (1W) and two water (2W) paths for the proton transfer (PT) step. This issue has been explored before by energy minimization with implicit solvent models and by non-systematic QM/MM energy minimization, as well as by non-systematic free energy mapping. However, no study has provided the needed reliable 2D (3D) surfaces which are necessary for reaching concrete conclusions. Our study generated in a systematic way the 2D (3D) free energy maps for several relevant systems, comparing the results of QM(ai)/MM and QM(ai)/implicit solvent surfaces, and provides an advanced description of the relevant energetics. It is found that the 1W path for the hydrolysis of methyl diphosphate (MDP) trianion is 6–9 kcal/mol higher than the 2W path. This difference becomes slightly larger in the presence of Mg2+ ion, since this ion reduces the pKa of the conjugated acid form of the phosphate oxygen that accepts the proton. Interestingly, the BLYP approach (which has been used extensively in some studies) gives much smaller difference between the 1W and 2W activation barriers. At any rate, it is worth to point out that the 2W transition state for the PT is not much higher that the common plateau that serves as the starting point of both the 1W and 2W PT paths. Thus, the calculated catalytic effects of proteins based on the 2W PT mechanistic models are not expected to be different from the catalytic effects predicted using the 1W PT mechanistic models calibrated on the observed barriers in solution (as was done in all of our previous EVB studies).