Is the Peptide Bond Formation Activated by Cu2+ Interactions? Insights from Density Functional Calculations

Metal cation binding to amino acids and peptides is a very active area of research due to their importance in many fields. With the advent of electrospray ion sources, metal cation complexes of amino acids and peptides can readily be generated in gas phase and studied by mass spectrometry techniques, from which structural and intrinsic reactivity information can be obtained. In particular, low energy collisionally activated dissociation experiments of Cu2+(Glycine)2 show that the [Cu2+(Glycine)2–H2O] complex, corresponding to the loss of a water molecule, is easily formed, which suggests the occurrence of an intracomplex condensation reaction leading to the formation of a peptide bond between two glycines (Seto and Stone, 1999). This reaction is similar to the Salt Induced Peptide Formation reaction proposed to take place in aqueous solution under prebiotic conditions (Rode, 1999). With the aim of getting a detailed understanding, at the molecular level, of the possible role that Cu2+ may have played in the formation of early peptides in the primitive earth, we have performed a theoretical mechanistic study, both in gas phase and in solution, on the condensation reaction between two glycine molecules in the presence of Cu2+ (Rimola et. al. 2007). Results show that the intracomplex condensation reaction in gas phase is associated to a very high free energy barrier due to the loss of metal coordination during the reaction. However, in aqueous solution, the important metal coordination changes observed in gas phase are largely attenuated. Moreover, the synergy between the interaction of glycines with Cu2+ and the presence of water molecules acting as proton-transfer helpers significantly lower the activation, largely favoring the formation of the peptide bond.