An ab initio analysis of the structure of l-tryptophan tautomers in microhydrated environments, in water and in hydrophobic solvents

The free energy of tryptophan (Trp) tautomers and conformers in different aqueous and non-aqueous environments has been calculated at the MP2/aug-cc-pVDZ//B3LYP/6-31+G(d,p) level of theory. Comparison with glycine (Gly) has been done in order to discuss the influence of the hydrophobic side chain. A detailed structural analysis has been first carried out to identify the relevant neutral (non-ionized) and zwitterionic (ionized) conformations. In water solution, explicit consideration of the first solvation shell (eight water molecules) has been found to be mandatory in order to correctly describe the system and therefore we have used a combined discrete–continuum solvation model to obtain free energies in this medium. Calculations in non-aqueous solvents have been done with the continuum model. The study shows that the hydrophobicity of the indole group of the Trp side chain does not influence much the tautomerization energy of the amino acid in water. Thus, the computed free energy of Trp tautomerization amounts −8.93 kcal/mol, which is not far from the theoretical and experimental values reported for the simplest natural amino acid glycine. Conversely, the free energy of transfer from water to cyclohexane has been estimated to 9.79 kcal/mol, which is much smaller than the energy reported before for glycine at a similar theoretical level (18.2 kcal/mol). The analysis of the results shows that the indole group yields a straightforward transfer of the neutral tautomer from the polar to the apolar phase, which requires only 0.86 kcal/mol instead of the 10 kcal/mol required for the neutral tautomer of glycine. The estimated energy of transfer is consistent with available experimental data for analogous systems.