Phenylalanine Oligomers and Fibrils: The Mechanism of Assembly and the Importance of Tetramers and Counterions

Phenylalanine is the only amino acid known to self-assemble into toxic fibrillar aggregates. An elevated concentration of phenylalanine in the blood can result in Phenylketonuria, a progressive mental retardation. Ion-mobility mass spectrometry is employed to investigate the structure and distribution of phenylalanine oligomers formed in the early stage of the aggregation cascade. The experimental cross sections indicate that phenyl-alanine self-assembles at neutral pH into oligomers composed of multiple layers of four monomers. The monomers arrange themselves to create a hydrophilic core made of zwitterionic termini and expose hydrophobic aromatic side chains to the outside. At high pH, the interactions between the neutral amino and negatively charged carboxylate of phenylalanine allow a minor population of ladder-like oligomers to be formed and detected in ion-mobility experiments. However, counterions such as ammonium rearrange those structures into the same structures observed at neutral pH. The cytotoxicity of Phe oligomers and fibrils may be due to favorable interactions between the hydrophobic exterior and the cell membrane and strong interactions between the hydrophilic core of Phe oligomers and ions, resulting in ion leakage and cellular damage.