The presence of an interacting water or methanol molecule has been shown to catalyze the 1,3-proton shift in a peptide linkage between the tautomers of protonated formamide and glycylglycylglycine. Density functional theory calculations at the B3LYP/6-31 ++ G(d,p) level of theory show that, for glycylglycylglycine, the forward barrier of this shift decreases from a free energy at 298 K of 39.6 kcal/mol in the absence of solvent to 26.7 kcal/mol in the presence of water and to 22.0 kcal/mol in the presence of methanol. Protonation at the amide nitrogen of the second residue results in a large increase in the C-N bond distance from 1.336 to 1.519 Angstrom, whereas protonation at the carbonyl oxygen leads to a decrease in the C-N bond distance from 1.336 to 1.321 Angstrom. Solvent-catalyzed tautomerism may play an important role in the fragmentation of electrosprayed, protonated peptides in the gas phase.