The appropriate quantum mechanical method for the investigation of enzymatic reactions, which involve oxocarbenium ions as reactive intermediates, is examined. 2-methoxy-tetrahydro-2H-pyran (1) was chosen as a model acetal for pyranose sugars, and its reactivity upon protonation of the glycosidic and the ring oxygen atom has been investigated using various density functional and post Haltree-Fock methods. Proton affinities calculated at the DFT levels of theory predict glycosidic protonation to be favorable by 2.5 kcal/mol. For ring-protonated 1, among the density functionals, a strong dependence of the molecular structure on the density functional employed is found. Structures obtained with the BLYP and B3LYP functionals are at variance with those from the ab initio methods, MP2 and CCSD, as shown by differences in bond lengths of more than 0.4 Angstrom for equivalent structures. By means of a valence bond analysis of the electron densities obtained at the DFT levels of theory, it is shown that this method dependence in this closed-shell species is caused by spurious self-interaction. This failure appears to be due to the subtle interplay between electron donating and accepting groups present in 1. The BHLYP functional is found to perform best among the functionals under investigation, for describing the hypersurfaces for protonated pyranose sugars.