Stabilization of Zwitterions in Solution: Phosphinic and Phosphonic Acid GABA Analogues

The influence of treatment of electron correlation, size of basis set and choice of solvation model on the
predicted stabilization of zwitterionic phosphinic and phosphonic acid γ-aminobutyric acid (GABA) analogues
is investigated using ab initio molecular orbital methods and density functional theory. Density functional
theory with the B3LYP functional and a composite basis set composed of the 6-31+G(2df) basis for phosphorus
atoms and the 6-31+G(d,p) basis set for all other atoms is found to give an acceptable tradeoff between
accuracy and computational expense. Either directly optimizing zwitterionic conformers within the conductor-like screening solvation model (COSMO) or pre-optimizing as dihydrates and then applying the COSMO
solvation model give an acceptable treatment of solvation in terms of determining stable solvated structures,
although directly optimizing within COSMO is simpler and less computationally expensive. With this protocol,
cis-constrained phosphinic and phosphonic acid GABA analogues, which exhibit lower affinities for GABAC
receptors, are found to possess only folded, intramolecularly hydrogen bonded low energy conformers. Trans-constrained analogues, on the other hand, exhibit higher affinities for GABAC receptors and are found to
exist only as partially folded stable conformers. Conformationally flexible analogues can attain folded, partially
folded or fully extended conformations and also have high biological activity. These results imply that the
partially folded conformation is likely to be the most biologically active.