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To clarify the role of aromatic residues on amyloid formation, the islet amyloid polypeptide 20\u201329 fragment [IAPP(20\u201329)], which contains a single aromatic residue (Phe 23), was adopted as a model. The side chain of residue 23 does not self\u2010associate in cross\u2010\u03b2 fibrils of IAPP(20\u201329) (Nielsen et al., Angew Chem Int Ed 2009;48:2118\u20132121), allowing investigation of the amyloidogenicity of aromatic amino acids in a context where direct \u03c0\u2013\u03c0 interactions do not occur. We prepared variants of IAPP(20\u201329) in which Tyr, Leu, Phe, pentafluorophenylalanine (F5\u2010Phe), Trp, cyclohexylalanine (Cha), \u03b1\u2010naphthylalanine (1\u2010Nap), or \u03b2\u2010naphthylalanine (2\u2010Nap) (in order of increasing peptide hydrophobicity) were incorporated at position 23 (SNNXGAILSS\u2010NH2), and the kinetic and thermodynamic effects of these mutations on cross\u2010\u03b2 self\u2010assembly were assessed. The Tyr, Leu, and Trp 23 variants failed to readily self\u2010assemble at concentrations up to 1.5 m<jats:italic>M<\/jats:italic>, while the Cha 23 mutant fibrillized with attenuated kinetics and similar thermodynamic stability relative to the wild\u2010type Phe 23 peptide. Conversely, the F5\u2010Phe, 1\u2010Nap, and 2\u2010Nap 23 variants self\u2010assembled at enhanced rates, forming fibrils with greater thermodynamic stability than the wild\u2010type peptide. These results indicate that the high amyloidogenicity of aromatic amino acids is a function of hydrophobicity, \u03b2\u2010sheet propensity, and planar geometry and not the ability to form stabilizing or directing \u03c0\u2013\u03c0 bonds. Proteins 2012;. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/prot.24007","type":"journal-article","created":{"date-parts":[[2011,12,6]],"date-time":"2011-12-06T09:38:10Z","timestamp":1323164290000},"page":"1053-1065","source":"Crossref","is-referenced-by-count":73,"title":["Role of amino acid hydrophobicity, aromaticity, and molecular volume on IAPP(20\u201329) amyloid self\u2010assembly"],"prefix":"10.1002","volume":"80","author":[{"given":"Todd M.","family":"Doran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa J.","family":"Kamens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia K.","family":"Byrnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley 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