The aromatic amino acid residue 4-(2-aminoethyl)-6-dibenzofuranopropanoic acid (1) nucleates antiparallel beta-sheet folding in tridecapeptides which subsequently self-assemble into fibrils. Residue 1 functions as a folding nucleator by facilitating intramolecular hydrogen bonding between the flanking alpha-amino acid residues and by favoring the formation of a hydrophobic cluster composed of the dibenzofuran skeleton and the hydrophobic side chains of the flanking alpha-amino acids. The hydrogen bonded hydrophobic cluster (i.e., -hydrophobic alpha-amino acid residue-1-hydrophobic alpha-amino acid residue-) nucleates beta-sheet folding in relatively small peptides that have a propensity to fold. The alpha-amino acid sequence design determines the self-association pathway and the resulting molecular architecture. The approach described here takes advantage of template driven hydrophobic clusters and template derived conformational biases to nucleate folding in small peptides, affording beta-sheets which subsequently self-associate into well-defined quaternary structures. This strategy allows significant alpha-amino acid sequence variations to be accommodated in the resulting beta-sheet-based macromolecular assembly without interfering with the folding pathway.