Cooperative salt bridge stabilization of gas-phase zwitterions in neutral arginine clusters

Both theory and experiment support a nonionic structure for monomeric arginine, with the zwitterionic structure predicted to be less stable by only 2.8 kcal/mol. We report here first principles quantum mechanics calculations (at the B3LYP/CCPVTZ(-F)²⁺//B3LYP/6-31G** level) which indicate that the neutral arginine dimer and trimer have all arginine in the zwitterionic state. The zwitterionic tautomer of the dimer is 10 kcal/mol more stable than the best nonionic form, even though each forms six hydrogen bonds involving both guanidinium groups interacting with the carboxylate groups. The most stable form of the neutral trimer of arginine has all arginine in the zwitterionic state, with a total of 12 hydrogen bonds involving interactions of the guanidinium and carboxylate groups between adjacent molecules. The additional coulomb energy derived from the salt bridges in the zwitterionic tautomers of the dimer and trimer more than compensates for the energetic cost of generating zwitterionic arginine. This is the first case in which small amino acid clusters are predicted to be stable in the zwitterionic form through self-solvation in the absence of a net charge.