title: Role of amino acid hydrophobicity, aromaticity, and molecular volume on IAPP(20-29) amyloid self-assembly.
abstract: Aromatic amino acids strongly promote cross-β amyloid formation; whether the amyloidogenicity of aromatic residues is due to high hydrophobicity and β-sheet propensity or formation of stabilizing π-π interactions has been debated. To clarify the role of aromatic residues on amyloid formation, the islet amyloid polypeptide 20-29 fragment [IAPP(20-29)], which contains a single aromatic residue (Phe 23), was adopted as a model. The side chain of residue 23 does not self-associate in cross-β fibrils of IAPP(20-29) (Nielsen et al., Angew Chem Int Ed 2009;48:2118-2121), allowing investigation of the amyloidogenicity of aromatic amino acids in a context where direct π-π interactions do not occur. We prepared variants of IAPP(20-29) in which Tyr, Leu, Phe, pentafluorophenylalanine (F5-Phe), Trp, cyclohexylalanine (Cha), α-naphthylalanine (1-Nap), or β-naphthylalanine (2-Nap) (in order of increasing peptide hydrophobicity) were incorporated at position 23 (SNNXGAILSS-NH2), and the kinetic and thermodynamic effects of these mutations on cross-β self-assembly were assessed. The Tyr, Leu, and Trp 23 variants failed to readily self-assemble at concentrations up to 1.5 mM, while the Cha 23 mutant fibrillized with attenuated kinetics and similar thermodynamic stability relative to the wild-type Phe 23 peptide. Conversely, the F5-Phe, 1-Nap, and 2-Nap 23 variants self-assembled at enhanced rates, forming fibrils with greater thermodynamic stability than the wild-type peptide. These results indicate that the high amyloidogenicity of aromatic amino acids is a function of hydrophobicity, β-sheet propensity, and planar geometry and not the ability to form stabilizing or directing π-π bonds.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Doran
authors.forename: Alissa J
authors.initials: AJ
authors.lastname: Kamens
authors.forename: Nadia K
authors.initials: NK
authors.lastname: Byrnes
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Nilsson
mesh_terms: D015057:1-Naphthylamine / Q000737:chemistry; D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000737:chemistry*; D000682:Amyloid / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry*; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
chemical_list: D024322:Amino Acids, Aromatic; D000682:Amyloid; C521761:IAPP(20-29) peptide; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D015057:1-Naphthylamine; D007930:Leucine