Origin of the transition state on the free energy surface: Intramolecular proton transfer reaction of glycine in aqueous solution

Not only to elucidate the origin of the reaction barrier in liquid phase, i.e., the free energy of activation, but also to locate the proper transition state (TS) for a chemical reaction, the molecular dynamics method and the free energy perturbation theory have been applied to the intramolecular proton transfer reaction of glycine in aqueous solution, i.e., the zwitterion (ZW), to the neutral form (NF). The potential energy surface varies drastically as its environment changes from gas phase to aqueous solution, and experimentally, the existence of an entropy barrier is also suggested due to the solvent molecules. In this study, it is reported that the TS on the free energy surface (FES) corresponds approximately to the geometry at s approximate to 0.66 amu(1/2) bohr, where s denotes the intrinsic reaction coordinate (IRC) for the gas-phase reaction, and therefore, the TS geometry is completely different from that for the gas phase. The free energy difference between ZW and NF is 8.46 +/- 1.45 kcal/mol, and then the free energy of activation of ZW is 16.85 +/- 1.36 kcal/mol at the temperature 300 K, both of which are in very good agreement with the experimental values. Further, the entropy contribution to the free energy change increases almost monotonously along the IRC, while the enthalpy contribution has a maximum at s approximate to 0.6 amu(1/2) bohr, being understood as the origin of the free energy of activation. By the interaction energy distribution and the radial distribution functions, it is shown that solvent water molecules interact with ZW more strongly than both TS and NF, especially at both the positive amino and negative carboxyl groups. Therefore, from a microscopic point of view, the reaction barrier in aqueous solution is clearly explained by the fact that as the forward reaction (ZW --> NF) proceeds, the Coulomb interaction between the charged groups of ZW and solvent water molecules becomes weaker while the intramolecular potential energy is stabilized compensatorily to form a free energy maximum.