Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta T1K 3M4, Canada.
J Phys Chem B. 2010 Jan 21;114(2):1104-13. doi: 10.1021/jp9098717.
Two-dimensional PCM-B3LYP/6-31+G(d) potential energy surfaces for the hydrolysis of the four natural 2'-deoxyribonucleosides (2'-deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and thymidine) are characterized using a model that includes both implicit (bulk) solvent effects and (three or four) explicit water molecules in the optimization routine. For the first time, the experimentally predicted dissociative (S(N)1) mechanism is found to be favored over the synchronous (S(N)2) pathway for all nucleosides studied. Due to the success of our model in stabilizing the charge-separated intermediates along the S(N)1 pathway, it is proposed that the new model presented here is the smallest system capable of generating the experimentally predicted oxacarbenium cation intermediate. We therefore stress that dissociative mechanisms should be studied with methodologies that account for the (bulk) environment in the optimization routine, where these effects are often only included as a correction to the energy in the current literature. In addition to accounting for charge stabilization through implicit solvation, nucleophile activation and leaving group stabilization should also be explicitly introduced into the model to further stabilize the system. Our work also emphasizes the importance of studying the Gibbs surface, which in some cases provides a better description of chemically important regions of the reaction surface or changes the calculated trend in the magnitude of dissociative barriers. In addition, it is proposed that the methodology presented in this study can be used to calculate uncatalyzed deglycosylation barriers for a range of DNA nucleosides, which when compared to the corresponding enzyme-catalyzed reactions, will allow the prediction of the rate enhancement (barrier reduction) due to the enzyme.
采用包括隐式（体相）溶剂效应和优化程序中（三个或四个）显式水分子的模型，对四种天然 2'-脱氧核苷（2'-脱氧腺苷、2'-脱氧鸟苷、2'-脱氧胞苷和胸苷）水解的二维 PCM-B3LYP/6-31+G(d)势能面进行了特征描述。首次发现，实验预测的解离（S(N)1）机制对于所有研究的核苷都优于同步（S(N)2）途径。由于我们的模型在 S(N)1 途径中稳定电荷分离中间体的成功，因此提出这里提出的新模型是能够生成实验预测的氧杂卡宾阳离子中间体的最小体系。因此，我们强调应该在优化程序中考虑（体相）环境的方法中研究解离机制，而在当前文献中，这些效应通常仅作为能量的校正项包括在内。除了通过隐式溶剂化来考虑电荷稳定外，还应将亲核试剂活化和离去基团稳定明确引入模型中，以进一步稳定体系。我们的工作还强调了研究吉布斯面的重要性，在某些情况下，吉布斯面可以更好地描述反应表面的化学重要区域或改变解离势垒大小的计算趋势。此外，提议本研究中提出的方法可用于计算一系列 DNA 核苷的无催化去糖基化势垒，与相应的酶催化反应相比，这将允许预测由于酶而导致的速率增强（势垒降低）。
