Conformational change of L-phenylalanine in fluorinated alcohol-water mixed solvents studied by IR, NMR, and MD simulations

Abstract

To clarify the unique solvation properties of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) on a biomolecule of L-phenylalanine (Phe), the solvation structure of Phe in HFIP-water mixed solvents at 70 mmol dm−3 has been observed over the entire range of HFIP mole fraction xHFIP using infrared (IR), 1H and 13C NMR techniques with a help of molecular dynamics (MD) simulation. The solvation structure of Phe in the HFIP solvents has been compared with that in 2-propanol (2-PrOH)-water mixed solvents and the structure of L-leucine (Leu) in both alcohol-water mixed solvents previously reported. The results from IR, NMR, and MD simulations showed that water molecules hydrogen-bonded with the Phe carboxylate group are gradually replaced by HFIP with increasing xHFIP. In contrast, the replacement of water molecules by HFIP on the Phe aminium group does not easily take place. These findings arise from the high electron acceptability and the very low electron donicity of the HFIP hydroxyl group due to the electron drawing of the six fluorine atoms. In the 2-PrOH solutions, the replacement of water on the carboxylate group by 2-PrOH less easily occurs with increasing x2-PrOH compared to HFIP because of the lower electron acceptability of 2-PrOH. The solvation for the Phe hydrophilic parts is similar to that of Leu. The most significant difference between HFIP and 2-PrOH was observed for the solvation of the Phe phenyl group. The hydrophobic hydration shell around the phenyl group is collapsed with increasing alcohol content in both alcohol solutions. Instead of water, the HFIP fluorine atoms significantly interact with the phenyl hydrogen atoms, whereas 2-PrOH molecules do not markedly approach the hydrogen atoms. The conformational change of Phe molecule against the dihedral angle of Cγ-Cβ–Cα-COO− takes place with increasing HFIP content, but does not with the increase in 2-PrOH. This is attributed to the steric hindrance between the large phenyl group and the carboxylate group remarkably solvated by HFIP molecules.