Influence of N7 Protonation on the Mechanism of the N-Glycosidic Bond Hydrolysis in 2'-Deoxyguanosine. A Theoretical Study

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• 作者：Raquel Rios-Font ; Luis Rodr&iacute ; guez-Santiago ; Joan Bertran ; Mariona Sodupe
• 刊名：Journal of Physical Chemistry B
• 出版年：2007
• 出版时间：May 31, 2007
• 年：2007
• 卷：111
• 期：21
• 页码：6071 - 6077
• 全文大小：400K
• 年卷期：v.111,no.21(May 31, 2007)
• ISSN：1520-5207

文摘

The influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosinehas been studied using density functional theory (DFT) methods. For the neutral system, two different pathways(with retention and inversion of configuration at the C1' anomeric carbon) have been found, both of themconsisting of two steps and involving the formation of a dihydrofurane-like intermediate. The Gibbs freeenergy barrier for the first step is very high in both cases (53 and 46 kcal/mol for the process with inversionand with retention, respectively). However, the N7-protonated system shows a very different mechanismwhich consists of two steps. The first one leads to the formation of an oxacarbenium ion intermediate, witha Gibbs free energy barrier of 27 kcal/mol, and the second one corresponds to the nucleophilic attack of thewater molecule to the oxacarbenium ion and takes place with a barrier of 1.3 kcal/mol. Thus, these resultsagree with a stepwise S_N1 mechanism (D_N*A_N), with a discrete intermediate formed between the leavinggroup and the nucleophile approach, and show that N7 protonation strongly catalyzes the hydrolysis of theN-glycosidic bond, making the guanine a better leaving group. Finally, kinetic isotope effects have beencalculated for the protonated system, and the results obtained are in very good agreement with experimentaldata for analogous systems.