Ab Initio Molecular Dynamics Free‐Energy Study of Microhydration Effects on the Neutral–Zwitterion Equilibrium of Phenylalanine

Abstract

The structures and relative energies of the most stable conformers of both naked and microsolvated phenylalanine, Phe.(H(2)O)(n)(n=0-3), are calculated by density functional theory. For selected structures, coordination-constrained ab initio molecular dynamics simulations determine the proton-transfer mechanism connecting neutral and zwitterionic forms of Phe. The associated free-energy profiles are calculated by thermodynamic integration. While no zwitterionic free-energy minimum is found for naked Phe, microsolvation is found to stabilize the zwitterionic form. For cluster sizes n > or = 3, the proton-transfer equilibrium shifts towards the zwitterionic structure for specific proton-transfer pathways. The energetically most favourable interconversion path between the neutral and zwitterionic forms is through a H(2)O bridge with free-energy barriers as low as 14.4 kJ mol(-1) for Phe.(H(2)O)(3). The free energy required for breaking a carboxylic OH bond involved in intramolecular hydrogen bonding is typically lower than in the water-assisted case. However, the resulting zwitterion turns out to be unstable with respect to the backward proton-transfer reaction.