The formation of 2-aminoacetamide from ammonia and glycine and N-glycylglycine from two glycine molecules with and without Mg2+, Cu2+, and Zn2+ cations as catalysts have been studied as model reactions for peptide bond formation using the B3LYP functional with 6−311+G(d,p) and 6−31G(d) basis sets. The B3LYP method was also used to characterize the nine gas–phase complexes of neutral glycine, its amide (2-aminoacetamide), and N-glycylglycine with Lewis acids Mg2+, Cu2+, and Zn2+, respectively. Further, the gas-phase hydration of metal-coordinated complexes of glycine, 2-aminoacetamide, and N-glycylglycine was also investigated. Finally, the effect of water on the structure and reactivity of the metal coordinated complexes was determined. Enthalpies and Gibbs energies for the stationary points of each reaction have been calculated to determine the thermodynamics of the reactions investigated. A substantial decrease in reaction enthalpies and Gibbs energies was found for glycine–ammonia and glycine–glycine reactions coordinated by Mg2+, Cu2+, and Zn2+ ions compared to those of the uncoordinated 2-aminoacetamide bond formation. The formation of a dipeptide is a more exothermic process than the creation of simple 2-aminoacetamide from glycine. The energetic effect of the transition metal ions Cu2+ and Zn2+ is of similar strength and more pronounced than that of the Mg2+ cation. The basicity order of the amides investigated shows the order: NH2CH2CO2H < NH2CH2CONH2 < NH2CH2CONHCH2CO2H. Interaction enthalpies and Gibbs energies of metal ion–amide complexes increase as Mg2+<Zn2+<Cu2+. In both reactant (glycine) and reaction products (2-aminoacetamide, N-glycylglycine) dihydration caused considerable reduction (about 200–500 kJ-mol−1) of the strength of the bifurcated metal–amide bonds. Solvent effects also reduce the reaction enthalpy and Gibbs energy of reactions under study.