On the mechanism of the N-glycosydic bond hydrolysis of 2′-deoxyguanosine: Insights from first principles calculations

R. Rios-Font, J. Bertran, M. Sodupe, L. Rodríguez-Santiago

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15 Citations (Scopus)

Abstract

The effect of the activation of the nucleobase (leaving group) or the activation of the water molecule (nucleophile) by a general acid or a general base on the hydrolysis of the N-glycosydic bond of 2′-deoxyguanosine has been analyzed by means of density functional methods. First, we have considered two limiting cases: (1) the activation of the guanine by protonation at N7 and (2) the nucleophile attack by a hydroxyl ion, to separately evaluate the two kinds of activation. Next, we have studied the simultaneous activation of the leaving group and the nucleophile by introducing models of amino acid residues such as a formic acid (HCOOH) and imidazolium (C3N2H5+), methylammonium (CH3NH3+) and formate (HCOO-) ions in the system. It is shown that protonation of the nucleobase greatly catalyzes the hydrolysis of the N-glycosydic bond, the reaction occurring through a stepwise (DN*AN) mechanism with a discrete oxocarbenium ion intermediate. However, when a H2O nucleophile molecule is activated by a formate anion, the reaction mechanism is a concerted ANDN but with different degrees of dissociative character of the transition structure depending on the acid that is activating the nucleobase. © 2010 Springer-Verlag.
Original languageEnglish
Pages (from-to)619-626
JournalTheoretical Chemistry Accounts
Volume128
Issue number4
DOIs
Publication statusPublished - 1 Feb 2011

Keywords

  • 2′-Deoxyguanosine
  • DFT
  • DNA repair mechanisms
  • Leaving group activation
  • N-glycosydic bond hydrolysis
  • Nucleophile activation

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