Amyloid fibril nucleation: effect of amino acid hydrophobicity.

We consider the nucleation of amyloid fibrils when the process occurs by direct polymerization of fully extended peptides (i.e., β-strands) into fibrils composed of successively layered β-sheets with alternating weak and strong hydrophobic surfaces. We extend our recently developed nucleation model (Kashchiev, D.; Cabriolu, R.; Auer, S. J. Am. Chem. Soc. 2013, 135, 1531-1539) to derive general expressions for the work to form such fibrils, the fibril solubility, the nucleation work, the equilibrium concentration of nuclei, and the fibril nucleation rate as explicit functions of the supersaturation of the protein solution. Analysis of these expressions illustrates the effect of increased asymmetry between the weak and strong hydrophobic β-sheet surfaces on the thermodynamics and kinetics of the polymerization process. In particular, the application of our theoretical framework to a simple model peptide system shows that lowering the hydrophobicity of one β-sheet surface can hamper protein fibrillation because the threshold concentration below which the fibril nucleation is practically arrested, and above which the process occurs vigorously--because then each monomer in the solution acts as a fibril nucleus--is shifted to higher concentrations. This effect is entirely due to the effect of asymmetry of the two hydrophobic β-sheet surfaces on the fibril solubility. In addition, with increasing asymmetry, the nucleation rate of one fibril polymorph becomes increasingly dominant, illustrating that there is a morphological selection between the two possible polymorphs.