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Role of amino acid hydrophobicity, aromaticity, and molecular volume on IAPP(20–29) amyloid self‐assembly
Author(s) -
Doran Todd M.,
Kamens Alissa J.,
Byrnes Nadia K.,
Nilsson Bradley L.
Publication year - 2012
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24007
Subject(s) - chemistry , aromatic amino acids , peptide , amyloid (mycology) , amino acid , aromaticity , residue (chemistry) , side chain , kinetics , mutant , stereochemistry , biochemistry , organic chemistry , molecule , inorganic chemistry , physics , gene , quantum mechanics , polymer
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 m M , 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. Proteins 2012;. © 2011 Wiley Periodicals, Inc.