Stabilization of Zwitterions in Solution: γ-Aminobutyric Acid (GABA)

The stabilization of γ-aminobutyric acid (GABA) zwitterions in aqueous solution is investigated at the HF/6-31+G*, B3LYP/6-31+G*, and MP2/6-31+G* levels of theory using explicitly bound water molecules to model short-range solvent effects and the conductor-like screening solvation model (COSMO) to estimate long-range solvent interactions. B3LYP and MP2 yield similar structures, relative energies and overall trends whereas HF theory does not provide a realistic description of GABA. The only approaches yielding zwitterionic structures consistent with experiment are the application of COSMO to GABA·2H 2 O or GABA·5H 2 O. An accurate description of aqueous phase GABA therefore requires both explicit interaction with at least two water molecules and long-range dielectric interactions with the solvent. Both types of interaction preferentially stabilize zwitterionic over neutral structures and stabilize extended zwitterions with respect to folded conformers. No stable neutral GABA·5H 2 O tautomers are obtained, suggesting that only zwitterionic forms of GABA are likely to be present in water. The extended GABA·5H 2 O zwitterions are postulated to be more stable in solution than the folded conformers and it is likely that a number of zwitterionic conformations are stable in water.