On Catalytic Preorganization in Oxyanion Holes: Highlighting the Problems with the Gas-Phase Modeling of Oxyanion Holes and Illustrating the Need for Complete Enzyme Models
On Catalytic Preorganization in Oxyanion Holes: Highlighting the Problems with the Gas-Phase Modeling of Oxyanion Holes and Illustrating the Need for Complete Enzyme Models
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DOI：
10.1021/jo100651s
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发表时间：
2010-10-01
影响因子：
3.6
通讯作者：
Warshel, A.
中科院分区：
文献类型：
--
作者：
Kamerlin, Shina C. L.;Chu, Zhen T.;Warshel, A.
氧阴离子空穴在催化酶反应中发挥着重要作用，但相应的能量学经常被误解。主要问题可能与静电预组织效应的非平凡性质有关，而不遵循相关的公式。也就是说，尽管氧阴离子空穴的能量学在早期研究（包括酶促反应和参比溶液反应）中已被完全量化，但这些研究的结果有时被忽视，并且在某些情况下，假设使用氧阴离子空穴的固定模型进行气相计算足以评估蛋白质中的相应效应。在此，我们对此问题进行了系统分析，阐明了通过两个固定水分子（或相关结构）模拟氧阴离子的相关问题。然后我们再次强调一点，氧阴离子空穴的影响主要是由于相关偶极子已经设定在稳定TS电荷的方向上，而溶液中相应的偶极子是随机定向的，导致需要付出非常大的重组能。简单地计算与相对固定的物种的相互作用能量并不能抓住这个关键点，考虑它可能有助于推进合理的酶设计。
Oxyanion holes play a major role in catalyzing enzymatic reactions, yet the corresponding energetics is frequently misunderstood. The main problem may be associated with the nontrivial nature of the electrostatic preorganization effect, without following the relevant formulation. That is, although the energetics of oxyanion holes have been fully quantified in early studies (which include both the enzymatic and reference solution reactions), the findings of these studies are sometimes overlooked, and, in some cases, it is assumed that gas-phase calculations with a fixed model of an oxyanion hole are sufficient for assessing the corresponding effect in the protein. Herein, we present a systematic analysis of this issue, clarifying the problems associated with modeling oxyanions by means of two fixed water molecules (or related constructs). We then re-emphasize the point that the effect of the oxyanion hole is mainly due to the fact that the relevant dipoles are already set in an orientation that stabilizes the TS charges, whereas the corresponding dipoles in solution are randomly oriented, resulting in the need to pay a very large reorganization energy. Simply calculating interaction energies with relatively fixed species cannot capture this crucial point, and considering it may help in advancing rational enzyme design.