title: Calculation of pKa values of nucleobases and the guanine oxidation products guanidinohydantoin and spiroiminodihydantoin using density functional theory and a polarizable continuum model.
abstract: An efficient computational method has been identified that uses B3LYP density functional theory, IEF-PCM solvation modeling with a modified UFF cavity, and Boltzmann weighting of tautomers to predict the site-specific and global pKa of DNA nucleobases and their oxidation products. The method has been used to evaluate the acidity of guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp), two highly mutagenic guanine oxidation products. The trend observed for the pKa values of Gh (9.64 and 8.15) is consistent with the experimentally observed values for guanidine cation (13.7) and hydantoin (9.16). The pKa1(calc) value for deprotonation of Sp cation (Sp+ --> Sp) is very close to the experimentally observed pKa1 for 8-oxoG and is consistent with the similarity in their structures. The data suggest that the imide (N7) proton in Sp is considerably more acidic than that in Gh, possibly due to the presence of the through-space electronic effects of the carbonyl group located at C6. This difference in the acidity of Gh and Sp may be an indication of their potential toxicity and mutagenicity in vivo and remains a fertile area for experimental study.
authors.affiliation: Department o di Chimica Generale ed Inorganica, Università di Parma, Parco Area della Scienze 1, 43100 Parma, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Verdolino
authors.forename: Roberto
authors.initials: R
authors.lastname: Cammi
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Munk
authors.forename: H Bernhard
authors.initials: HB
authors.lastname: Schlegel
mesh_terms: D006146:Guanidines / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006827:Hydantoins / Q000737:chemistry*; D008956:Models, Chemical; D010084:Oxidation-Reduction; D013141:Spiro Compounds / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D006146:Guanidines; D006827:Hydantoins; D013141:Spiro Compounds; C467338:guanidinohydantoin; C408822:spiroiminodihydantoin; D006151:Guanosine; D006147:Guanine