Rosta Edina, Kamerlin Shina C L, Warshel Arieh
Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089-1062, USA.
Biochemistry. 2008 Mar 25;47(12):3725-35. doi: 10.1021/bi702106m. Epub 2008 Feb 29.
The hydrolysis of phosphate esters is crucially important to biological systems, being involved in, among other things, signaling, energy transduction, biosynthesis, and the regulation of protein function. Despite this, there are many questions that remain unanswered in this important field, particularly with regard to the preferred mechanism of hydrolysis of phosphate esters, which can proceed through any of multiple pathways that are either associative or dissociative in nature. Previous comparisons of calculated and observed linear free energy relationships (LFERs) for phosphate monoester dianions with different leaving groups showed that the TS character gradually changes from associative to dissociative with the increasing acidity of the leaving group, while reproducing the experimental LFER. Here, we have generated ab initio potential energy surfaces for the hydrolysis of phosphate diesters in solution, with a variety of leaving groups. Once again, the reaction changes from a compact concerted pathway to one that is more expansive in character when the acidity of the leaving group increases. When such systems are examined in solution, it is essential to take into consideration the contribution of solute to the overall activation entropy, which remains a major computational challenge. The popular method of calculating the entropy using a quasi-harmonic approximation appears to markedly overestimate the configurational entropy for systems with multiple occupied energy wells. We introduce an improved restraint release approach for evaluating configurational entropies and apply this approach to our systems. We demonstrate that when this factor is taken into account, it is possible to reproduce the experimental LFER for this system with reasonable accuracy.
磷酸酯的水解对生物系统至关重要，它参与了信号传导、能量转导、生物合成以及蛋白质功能调节等诸多过程。尽管如此，在这个重要领域仍有许多问题未得到解答，特别是关于磷酸酯水解的首选机制，其可以通过本质上为缔合或解离的多种途径中的任何一种进行。先前对具有不同离去基团的磷酸单酯二价阴离子的计算和观察到的线性自由能关系（LFERs）的比较表明，随着离去基团酸度的增加，过渡态（TS）特征逐渐从缔合变为解离，同时重现了实验LFER。在这里，我们利用多种离去基团生成了溶液中磷酸二酯水解的从头算势能面。再次，当离去基团的酸度增加时，反应从紧密协同途径转变为更具扩展性的途径。当在溶液中研究此类系统时，必须考虑溶质对整体活化熵的贡献，这仍然是一个主要的计算挑战。使用准谐波近似计算熵的常用方法似乎明显高估了具有多个占据能阱的系统的构型熵。我们引入了一种改进的约束释放方法来评估构型熵，并将此方法应用于我们的系统。我们证明，当考虑到这个因素时，有可能以合理的精度重现该系统的实验LFER。
