Proton affinities and N-glycosidic bond stabilities of hydroxyl radical modified adenosine

Abstract

The stabilities of the N-glycosidic bonds of three adenosine analogs were studied by means of ab inito quantum chemistry methods. The N9-methoxymethyl derivatives were studied as model compounds representing nucleosides. The Gibbs free energies were estimated for all possible mono- and double-protonated tautomers of 2-OH-adenosine (2a), 2-oxo-adenosine (2b), 8-OH-adenosine (3a), 8-oxo-adenosine (3b) and fapy-adenosine (4). The solvent effect was estimated based on an SCI-PCM model. The presented results suggest that for C2 modified adenosine analogs the most basic atom is the N3 centre of 2-oxo-adenosine followed by the N1 atom of 2-OH-adenosine. Adenosine modified at C8 is mostly protonated on N1, irrespective of the tautomeric form, but the keto form is much more likely than 8-enol one. In the case of fapy-adenosine protonation takes place mainly on N3. The rest of the electronegative centres of all studied compounds are in practice not protonated. At very low pH, 2-OH-Ade is mostly represented by N3 and N7 double protonated forms. In the case of 8-oxo-adenosine and fapy-adenosine in the second protonation reaction O8 may be the active centre. For 8-oxo-adenosine there are mainly two products of double protonation: [dAB2-HO8N1]2+ and [dAB2-HO8N3]2+. Fapy-adenosine is also protonated at O8, which led to the [dAC-HN3O8]2+ cation with 99.9% probability. Mutual proton attack on N1 and O8 centres is much less probable (0.1%).