Theoretical investigation of the neutral/zwitterionic equilibrium of gamma-aminobutyric acid (GABA) conformers in aqueous solution

Since gamma-aminobutyric acid does not form a stable zwitterionic species i n the gas phase, as calculated at the HF/6-311++G** level, the GABA.2H(2)O system was optimized for several neutral and zwitterionic GABA tantomers/co nformers. The obtained molecular geometries and vibrational frequencies det ermined for the dihydrates reflect structural changes for GABA due to close and strongly bound water molecules. By use of GABA geometries optimized in the dihydrates, relative free energies of different species in aqueous sol ution were calculated. MP2/6-311++G**//HF/6-311++G"* energy values show tha t the neutral form is strongly preferred over the zwitterionic one for the isolated GABA species. The neutral tautomer, which is most stable in the ga s phase, is only marginally changed by hydration; it is without an intramol ecular hydrogen bond and has nearly gauche-gauche arrangements, 54 and -83 degrees, for the NCCC and the CCCC torsion angles, respectively, as determi ned in the dihydrate; In aqueous solution the zwitterionic structure is dom inant. Comparison of cyclic gauche-gauche forms and a partially extended, g auche-trans structure indicates the preference of the more extended form. T his structure differs from the trans-gauche zwitterionic conformer found fo r GABA by X-ray experiments in the crystalline phase. The experimental GABA conformer is not stable either in the isolated form or in the gas-phase di hydrate. It is, however, more stable by about 6.5 kcal/mol than the gas-pha se gauche-trans form, as turned out in a restricted geometry optimization. Such a large internal stabilization may allow the existence (even preferenc e) of the experimental zwitterionic GABA structure in aqueous solution if s olvent effects are preferable. Partition of GABA between water and chlorofo rm is not favored. At least 7.5 kcal/mol free energy increase is required i f the zwitterion either directly or after transformation to a neutral form would leave the aqueous phase and enter chloroform. This result. supports t he experimental finding that GABA does not cross the blood-brain barrier.