3334 Phys. Chem. Chem. Phys., 2011, 13, 3334–3343 This journal is c the Owner Societies 2011 Cite this: Phys. Chem. Chem. Phys., 2011, 13, 3334–3343 The impact of protonation and deprotonation of 3-methyl-2 0 - deoxyadenosine on N-glycosidic bond cleavage Ali Ebrahimi,* Mostafa Habibi-Khorassani and Sophia Bazzi Received 22nd July 2010, Accepted 25th November 2010 DOI: 10.1039/c0cp01279c The enzyme–substrate contacts that are believed to be involved in depurination by proton transfer have been modelled by protonation and deprotonation of 3-methyl-2 0 -deoxyadenosine (3-MDA) using quantum mechanical calculations in the gas-phase and solution media. The change in the charge distribution on the sugar ring and nucleobase that is introduced by the protonation and deprotonation strongly affects the N-glycosidic bond length. The unimolecular cleavage and hydrolysis of the N-glycosidic bond, involving D N *A N and A N D N pathways, have been considered at several levels of theory. The trend in the energy barriers is A N D N > cleavage > D N *A N . All probable proton transfer reactions resulting from enzyme–substrate contacts do not facilitate the N-glycosidic bond cleavage of 3-MDA. The deprotonation of 3-MDA that may result from the interaction between H6 and enzyme do not facilitate bond cleavage. The protonation at N7 induces more positive charge on the sugar ring and further facilitates the depurination relative to the protonation at N1. The changes in the charges calculated on the ribose and nucleobase are in good relationship with the C1 0 –C2 0 , C1 0 –O4 0 , and N-glycosidic bond lengths along the cleavage. The change in energy barrier DE of glycosidic bond cleavage from the gas-phase to solution media strongly depends on the charge of the species. Introduction Deoxyribonucleic acid (DNA) is vulnerable to certain types of disruptive forces like alkylation, especially in adenine and guanine bases. 1 Alkylated bases often pair incorrectly and may cause a transition mutation on subsequent rounds of replication. 1 The cleavage of N-glycosidic bond in deoxynucleosides and nucleosides is a common reaction in nucleobase salvage 2–4 and DNA repair. 5,6 Depurination is a process in which the purine base (adenine or guanine) is removed from the deoxyribose sugar by hydrolysis of the N-glycosidic bond. Methylated nucleotides (a sort of DNA damaged bases) and the N-glycosidic bond cleavage have previously been studied from both experimental 7–25 and theoretical 26–30 points of view. The DNA glycosylases correspond to remarkable enzyme classes that recognize and remove damaged DNA bases as the first step in the base excision repair pathway. 31,32 3-Methyl adenine DNA glycosylase I (TAG) is an alkylated purine- specific DNA glycosylase which is unique for 3-methyl-2 0 - deoxyadenosine (3-MDA) and 3-methyl deoxyguanosine. 33 The 3-MDA binding pocket of TAG is given in Scheme 1. These contacts could potentially enable proton transfer from adenine to enzyme and vise versa. MutY that is an adenine-specific DNA glycosylase has an active site, aspartic acid (Asp138), and acts as a general acid catalyst to protonate (presumably N7) and to stabilize the leaving group in the N-glycosidic bond cleavage reaction. 34 Purinespecific DNA glycosylases appear to use general acid catalysis to stabilize the purine leaving group. 34,35 As can be seen in Scheme 1, TAG has glutamic acid (Glu38) and tyrosine residues that suggested to form hydrogen bonds with the N1, N6 and N7 positions of 3-MDA, in which N1 and N7 are proton acceptors and N6 is a proton donor. In the cases that Scheme 1 3-MDA binding pocket of TAG. Department of Chemistry, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran. E-mail: Ebrahimi@hamoon.usb.ac.ir PCCP Dynamic Article Links www.rsc.org/pccp PAPER Published on 26 January 2011. Downloaded by Masarykova Univerzita V Brne on 10/03/2015 16:26:43. View Article Online / Journal Homepage / Table of Contents for this issue