An AM1 and PM3 molecular orbital and self-consistent reaction-field study of the aqueous solvation of glycine, alanine and proline in their neutral and zwitterionic forms

Abstract

Two solvation models based on the semi-empirical AM1 and PM3 SCF–MO Hamiltonians are evaluated for the neutral and zwitterionic forms of the amino acids glycine, alanine and proline. The predicted PM3 solvation energetics for the solvated glycine zwitterion based on a supermolecule comprising up to 15 water molecules are in reasonable agreement with experiment. The calculated PM3 solvent structures agree broadly with previously proposed models, but several new aspects are revealed. The corresponding AM1 model shows the expected preference for bifurcation in the solvent structure and several significant differences to PM3 in the solvation energetics. Energies and geometries obtained using a self-consistent reaction-field (SCRF) model assuming a spherical (isotropic) solvent cavity are compared with the supermolecule approach. Whilst SCRF solvation energies are particularly sensitive to the size of the cavity radius used, geometrical changes involving hydrogen bonding compare well with the supermolecule model. A combined supermolecule/SCRF approach supports the hypothesis that the fifteen-water supermolecules are close to the bulk solvation limit. The failure of both the AM1 and the PM3 solvation models to correctly reproduce the low barrier observed for aqueous intramolecular proton transfer in glycine is discussed.